241 results on '"Vinetz JM"'
Search Results
2. Pregnancy outcome in relation to treatment of murine typhus and scrub typhus infection: a fever cohort and a case series analysis
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McGready, R, Prakash, JA, Benjamin, SJ, Watthanaworawit, W, Anantatat, T, Tanganuchitcharnchai, A, Ling, Clare, Tan, SO, Ashley, EA, Pimanpanarak, M, Blacksell, Stuart, Day, Nicholas, Singhasivanon, P, White, Nicholas, Nosten, Francois, Paris, Daniel, Vinetz, JM, and Vinetz, J
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Bacterial Diseases ,Maternal Health ,Scrub typhus ,Pediatrics ,Miscarriage ,0302 clinical medicine ,Pregnancy ,Zoonoses ,Medicine and Health Sciences ,030212 general & internal medicine ,Pregnancy Complications, Infectious ,Obstetrics ,lcsh:Public aspects of medicine ,Pregnancy Outcome ,Relapsing Fever ,Typhus, Endemic Flea-Borne ,Thailand ,3. Good health ,Typhus of Rickettsiae ,Infectious Diseases ,Veterinary Diseases ,Cohort ,Female ,medicine.symptom ,Research Article ,Neglected Tropical Diseases ,Cohort study ,Adult ,medicine.medical_specialty ,lcsh:Arctic medicine. Tropical medicine ,Adolescent ,Fever ,lcsh:RC955-962 ,030231 tropical medicine ,Murine typhus ,Young Adult ,03 medical and health sciences ,medicine ,Humans ,Retrospective Studies ,business.industry ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,Retrospective cohort study ,lcsh:RA1-1270 ,Tropical Diseases ,medicine.disease ,bacterial infections and mycoses ,Surgery ,Low birth weight ,Scrub Typhus ,Miscarriage and Stillbirth ,Women's Health ,Veterinary Science ,Neonatology ,business - Abstract
Background There is a paucity of published reports on pregnancy outcome following scrub and murine typhus despite these infections being leading causes of undifferentiated fever in Asia. This study aimed to relate pregnancy outcome with treatment of typhus. Methodology/Principal Findings Data were analyzed from: i) pregnant women with a diagnosis of scrub and/or murine typhus from a fever cohort studies; ii) case series of published studies in PubMed using the search terms “scrub typhus” (ST), “murine typhus” (MT), “Orientia tsutsugamushi”, “Rickettsia tsutsugamushi”, “Rickettsia typhi”, “rickettsiae”, “typhus”, or “rickettsiosis”; and “pregnancy”, until February 2014 and iii) an unpublished case series. Fever clearance time (FCT) and pregnancy outcome (miscarriage and delivery) were compared to treatment. Poor neonatal outcome was a composite measure for pregnancies sustained to 28 weeks or more of gestation ending in stillbirth, preterm birth, or delivery of a growth restricted or low birth weight newborn. Results There were 26 women in the fever cohort. MT and ST were clinically indistinguishable apart from two ST patients with eschars. FCTs (median [range] hours) were 25 [16–42] for azithromycin (n = 5), 34 [20–53] for antimalarials (n = 5) and 92 [6–260] for other antibiotics/supportive therapy (n = 16). There were 36.4% (8/22) with a poor neonatal outcome. In 18 years, 97 pregnancies were collated, 82 with known outcomes, including two maternal deaths. Proportions of miscarriage 17.3% (14/81) and poor neonatal outcomes 41.8% (28/67) were high, increasing with longer FCTs (p = 0.050, linear trend). Use of azithromycin was not significantly associated with improved neonatal outcomes (p = 0.610) Conclusion The published ST and MT world literature amounts to less than 100 pregnancies due to under recognition and under diagnosis. Evidence supporting the most commonly used treatment, azithromycin, is weak. Collaborative, prospective clinical trials in pregnant women are urgently required to reduce the burden of adverse maternal and newborn outcomes and to determine the safety and efficacy of antimicrobial treatment., Author Summary Typhus is an under-recognised and under-studied public health problem in Asia. In rural areas of Southeast Asia murine and scrub typhus are probably the most common treatable cause of fever. The estimated number of scrub typhus cases in Southeast Asia, more than 1 million yearly, results in approximately 50–80,000 deaths per year. Treatment delays due to lack of appropriate diagnostics and lack of awareness lead to a substantial health and economic impact in the one of the world's most densely populated regions. Only 97 cases in pregnancy are available from the published world literature over the past 18 years. Only 82 of these had known outcomes, including two maternal deaths. The proportion of poor neonatal outcome including stillbirth, prematurity and low birth weight was high occurring in more than 40% of pregnancies, and higher when the fever clearance time was longer. While poor neonatal outcomes were observed with all antibiotics prescribed, azithromycin appeared to be associated with shorter fever clearance times but this was not statistically significant. Evidence to support the use of azithromycin is weak. The correct antimicrobial or combination for undifferentiated fever in pregnant women in Southeast Asia is unknown.
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- 2016
3. Case report: Cysticercosis with an orbital tropism in twins
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Lee, BW, Kumar, UR, Kikkawa, DO, Alameddine, RM, Korn, BS, Lin, JH, Amaro, DE, Lowe, MC, Hilger, PA, and Vinetz, JM
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Copyright © 2015 by The American Society of Tropical Medicine and Hygiene. Two fraternal twin sisters developed cysticercosis localizing to the right lateral orbit over the same period after a presumed common-source exposure in China. This case demonstrates that cysticercosis can be related to travel. Similar temporal and spatial occurrences of these infections suggest a genetic tropism of the infecting organism in these twins.
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- 2015
4. A Global Research Agenda for Leptospirosis
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Cachay, ER and Vinetz, JM
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Risk Factors ,Humans ,Leptospirosis ,Article - Abstract
Leptospirosis is a zoonotic spirochetal disease of global importance. This disease continues to have a major impact on people living in urban and rural areas of developing countries with inestimable morbidity and mortality. Funding for research and control efforts is currently haphazard, not organized and not effective for public health efforts, primarily because there are no concerted, ongoing international efforts to assess the impact of leptospirosis on human health. Major issues in the field need to be addressed to develop strategies of control, amelioration and treatment. These include the following: mechanisms of naturally acquired and vaccine-induced protective immunity against clinical leptospirosis; mechanisms of severe leptospirosis pathogenesis; standardized, precise and simplified taxonomy of Leptospira relevant to disease manifestations, transmission and control; effective adjunct treatments in addition to antimicrobials; and environmental assessment for risk of leptospirosis transmission and relevant mammalian reservoirs. Once effective ongoing, collaborative international efforts to assess the impact of leptospirosis on human and veterinary health are underway, appropriate mobilization of clinical and public health research funding will follow.
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- 2005
5. Oroya Fever and Verruga Peruana: Bartonelloses Unique to South America
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Vinetz, JM, Minnick, MF, Anderson, BE, Lima, A, Battisti, JM, Lawyer, PG, and Birtles, RJ
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Veterinary medicine ,Review ,Pathogenesis ,Pathology and Laboratory Medicine ,Bartonella bacilliformis ,Medicine and Health Sciences ,0303 health sciences ,Ecology ,biology ,lcsh:Public aspects of medicine ,Neglected Diseases ,health_and_wellbeing ,Bacterial Pathogens ,3. Good health ,Infectious Diseases ,Medical Microbiology ,Host-Pathogen Interactions ,Bartonella Infection ,Bartonella ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,Secondary infection ,Zoology ,Microbiology ,Microbial Ecology ,03 medical and health sciences ,Verruga peruana ,Microbial Control ,Bartonella Infections ,parasitic diseases ,medicine ,Animals ,Humans ,Microbial Pathogens ,030304 developmental biology ,030306 microbiology ,Public Health, Environmental and Occupational Health ,Oroya ,Biology and Life Sciences ,Outbreak ,lcsh:RA1-1270 ,Bacteriology ,Carrion's disease ,South America ,biology.organism_classification ,medicine.disease ,Insect Vectors ,Emerging Infectious Diseases ,Psychodidae - Abstract
Bartonella bacilliformis is the bacterial agent of Carrión's disease and is presumed to be transmitted between humans by phlebotomine sand flies. Carrión's disease is endemic to high-altitude valleys of the South American Andes, and the first reported outbreak (1871) resulted in over 4,000 casualties. Since then, numerous outbreaks have been documented in endemic regions, and over the last two decades, outbreaks have occurred at atypical elevations, strongly suggesting that the area of endemicity is expanding. Approximately 1.7 million South Americans are estimated to be at risk in an area covering roughly 145,000 km2 of Ecuador, Colombia, and Peru. Although disease manifestations vary, two disparate syndromes can occur independently or sequentially. The first, Oroya fever, occurs approximately 60 days following the bite of an infected sand fly, in which infection of nearly all erythrocytes results in an acute hemolytic anemia with attendant symptoms of fever, jaundice, and myalgia. This phase of Carrión's disease often includes secondary infections and is fatal in up to 88% of patients without antimicrobial intervention. The second syndrome, referred to as verruga peruana, describes the endothelial cell-derived, blood-filled tumors that develop on the surface of the skin. Verrugae are rarely fatal, but can bleed and scar the patient. Moreover, these persistently infected humans provide a reservoir for infecting sand flies and thus maintaining B. bacilliformis in nature. Here, we discuss the current state of knowledge regarding this life-threatening, neglected bacterial pathogen and review its host-cell parasitism, molecular pathogenesis, phylogeny, sand fly vectors, diagnostics, and prospects for control.
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- 2014
6. Leptospirosis is everywhere, just have to know what to look for. But how?
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Vinetz, JM, primary
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- 2004
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7. A global research agenda for leptospirosis.
- Author
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Cachay ER and Vinetz JM
- Abstract
Leptospirosis is a zoonotic spirochetal disease of global importance. This disease continues to have a major impact on people living in urban and rural areas of developing countries with inestimable morbidity and mortality. Funding for research and control efforts is currently haphazard, not organized and not effective for public health efforts, primarily because there are no concerted, ongoing international efforts to assess the impact of leptospirosis on human health. Major issues in the field need to be addressed to develop strategies of control, amelioration and treatment. These include the following: mechanisms of naturally acquired and vaccine- induced protective immunity against clinical leptospirosis; mechanisms of severe leptospirosis pathogenesis; standardized, precise and simplified taxonomy of Leptospira relevant to disease manifestations, transmission and control; effective adjunct treatments in addition to antimicrobials; and environmental assessment for risk of leptospirosis transmission and relevant mammalian reservoirs. Once effective ongoing, collaborative international efforts to assess the impact of leptospirosis on human and veterinary health are underway, appropriate mobilization of clinical and public health research funding will follow. [ABSTRACT FROM AUTHOR]
- Published
- 2005
8. Costs of testing for ocular Chlamydia trachomatis infection compared to mass drug administration for trachoma in the Gambia: application of results from the PRET study
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Harding-Esch, Emma, Jofre-Bonet, Mireia, Dhanjal, Jaskiran K., Burr, Sarah, Edwards, Tansy, Holland, Martin, Sillah, Ansumana, West, Sheila, Lietman, Tom, Keenan, Jeremy, Mabey, David, Bailey, Robin, and Vinetz, JM
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Male ,Trachoma ,lcsh:Arctic medicine. Tropical medicine ,lcsh:RC955-962 ,lcsh:Public aspects of medicine ,HB ,Chlamydia trachomatis ,lcsh:RA1-1270 ,Azithromycin ,Middle Aged ,Anti-Bacterial Agents ,Child, Preschool ,Humans ,Mass Screening ,Female ,Gambia ,Child ,skin and connective tissue diseases ,Research Article ,RC - Abstract
Background Mass drug administration (MDA) treatment of active trachoma with antibiotic is recommended to be initiated in any district where the prevalence of trachoma inflammation, follicular (TF) is ≥10% in children aged 1–9 years, and then to continue for at least three annual rounds before resurvey. In The Gambia the PRET study found that discontinuing MDA based on testing a sample of children for ocular Chlamydia trachomatis(Ct) infection after one MDA round had similar effects to continuing MDA for three rounds. Moreover, one round of MDA reduced disease below the 5% TF threshold. We compared the costs of examining a sample of children for TF, and of testing them for Ct, with those of MDA rounds. Methods The implementation unit in PRET The Gambia was a census enumeration area (EA) of 600–800 people. Personnel, fuel, equipment, consumables, data entry and supervision costs were collected for census and treatment of a sample of EAs and for the examination, sampling and testing for Ct infection of 100 individuals within them. Programme costs and resource savings from testing and treatment strategies were inferred for the 102 EAs in the study area, and compared. Results Census costs were $103.24 per EA plus initial costs of $108.79. MDA with donated azithromycin cost $227.23 per EA. The mean cost of examining and testing 100 children was $796.90 per EA, with Ct testing kits costing $4.80 per result. A strategy of testing each EA for infection is more expensive than two annual rounds of MDA unless the kit cost is less than $1.38 per result. However stopping or deciding not to initiate treatment in the study area based on testing a sample of EAs for Ct infection (or examining children in a sample of EAs) creates savings relative to further unnecessary treatments. Conclusion Resources may be saved by using tests for chlamydial infection or clinical examination to determine that initial or subsequent rounds of MDA for trachoma are unnecessary., Author Summary Trachoma, caused by infection with a bacterium (chlamydia) is controlled by mass drug administration (MDA), which is recommended yearly for districts in which a trachoma problem has been found to exist. The decision, after several rounds, that MDA is no longer needed is currently based on clinical signs of trachoma, but these are an unreliable indicator of infection. The PRET study, in the Gambia, found that tests for infection could be used to show that subsequent rounds of MDA were redundant. This paper shows, by estimating the costs, that testing children in a sample of census districts for infection can save resources compared to (unnecessary) rounds of MDA.
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- 2015
9. An atlas of human vector-borne microbe interactions reveals pathogenicity mechanisms.
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Hart TM, Sonnert ND, Tang X, Chaurasia R, Allen PE, Hunt JR, Read CB, Johnson EE, Arora G, Dai Y, Cui Y, Chuang YM, Yu Q, Rahman MS, Mendes MT, Rolandelli A, Singh P, Tripathi AK, Ben Mamoun C, Caimano MJ, Radolf JD, Lin YP, Fingerle V, Margos G, Pal U, Johnson RM, Pedra JHF, Azad AF, Salje J, Dimopoulos G, Vinetz JM, Carlyon JA, Palm NW, Fikrig E, and Ring AM
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- Humans, Animals, Lyme Disease microbiology, Vector Borne Diseases, Host Microbial Interactions, Borrelia burgdorferi pathogenicity, Borrelia burgdorferi metabolism, Host-Pathogen Interactions
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Vector-borne diseases are a leading cause of death worldwide and pose a substantial unmet medical need. Pathogens binding to host extracellular proteins (the "exoproteome") represents a crucial interface in the etiology of vector-borne disease. Here, we used bacterial selection to elucidate host-microbe interactions in high throughput (BASEHIT)-a technique enabling interrogation of microbial interactions with 3,324 human exoproteins-to profile the interactomes of 82 human-pathogen samples, including 30 strains of arthropod-borne pathogens and 8 strains of related non-vector-borne pathogens. The resulting atlas revealed 1,303 putative interactions, including hundreds of pairings with potential roles in pathogenesis, including cell invasion, tissue colonization, immune evasion, and host sensing. Subsequent functional investigations uncovered that Lyme disease spirochetes recognize epidermal growth factor as an environmental cue of transcriptional regulation and that conserved interactions between intracellular pathogens and thioredoxins facilitate cell invasion. In summary, this interactome atlas provides molecular-level insights into microbial pathogenesis and reveals potential host-directed targets for next-generation therapeutics., Competing Interests: Declaration of interests N.W.P. and A.M.R. are inventors of a patent describing the BASEHIT technique., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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10. Genomic surveillance of malaria parasites in an indigenous community in the Peruvian Amazon.
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Cabrera-Sosa L, Nolasco O, Kattenberg JH, Fernandez-Miñope C, Valdivia HO, Barazorda K, Arévalo de Los Rios S, Rodriguez-Ferrucci H, Vinetz JM, Rosanas-Urgell A, Van Geertruyden JP, Gamboa D, and Delgado-Ratto C
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- Peru epidemiology, Humans, Female, Male, Child, Adult, Antimalarials therapeutic use, Antimalarials pharmacology, Adolescent, Drug Resistance genetics, Middle Aged, Indigenous Peoples genetics, Young Adult, Child, Preschool, Genomics methods, Genetic Variation, Antigens, Protozoan genetics, Plasmodium falciparum genetics, Plasmodium falciparum isolation & purification, Plasmodium vivax genetics, Plasmodium vivax isolation & purification, Malaria, Falciparum epidemiology, Malaria, Falciparum parasitology, Malaria, Falciparum transmission, Malaria, Vivax epidemiology, Malaria, Vivax parasitology, Malaria, Vivax transmission, Protozoan Proteins genetics
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Hard-to-reach communities represent Peru's main challenge for malaria elimination, but information about transmission in these areas is scarce. Here, we assessed Plasmodium vivax (Pv) and P. falciparum (Pf) transmission dynamics, resistance markers, and Pf hrp2/3 deletions in Nueva Jerusalén (NJ), a remote, indigenous community in the Peruvian Amazon with high population mobility. We collected samples from November 2019 to May 2020 by active (ACD) and passive case detection (PCD) in NJ. Parasites were identified with microscopy and PCR. Then, we analyzed a representative set of positive-PCR samples (Pv = 68, Pf = 58) using highly-multiplexed deep sequencing assays (AmpliSeq) and compared NJ parasites with ones from other remote Peruvian areas using population genetics indexes. The ACD intervention did not reduce malaria cases in the short term, and persistent malaria transmission was observed (at least one Pv infection was detected in 96% of the study days). In Nueva Jerusalen, the Pv population had modest genetic diversity (He = 0.27). Pf population had lower diversity (He = 0.08) and presented temporal clustering, one of these clusters linked to an outbreak in February 2020. Moreover, Pv and Pf parasites from NJ exhibited variable levels of differentiation (Pv Fst = 0.07-0.52 and Pf Fst = 0.11-0.58) with parasites from other remote areas. No artemisin resistance mutations but chloroquine (57%) and sulfadoxine-pyrimethamine (35-67%) were detected in NJ's Pf parasites. Moreover, pfhrp2/3 gene deletions were common (32-50% of parasites with one or both genes deleted). The persistent Pv transmission and the detection of a Pf outbreak with parasites genetically distinct from the local ones highlight the need for tailored interventions focusing on mobility patterns and imported infections in remote areas to eliminate malaria in the Peruvian Amazon., (© 2024. The Author(s).)
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- 2024
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11. Computational reassessment of RNA-seq data reveals key genes in active tuberculosis.
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Arya R, Shakya H, Chaurasia R, Kumar S, Vinetz JM, and Kim JJ
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- Humans, Protein Interaction Maps genetics, RNA-Seq, Computational Biology methods, Gene Expression Profiling methods, ROC Curve, Gene Regulatory Networks, Databases, Genetic, Biomarkers metabolism, Gene Ontology, Tuberculosis genetics
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Background: Tuberculosis is a serious life-threatening disease among the top global health challenges and rapid and effective diagnostic biomarkers are vital for early diagnosis especially given the increasing prevalence of multidrug resistance., Methods: Two human whole blood microarray datasets, GSE42826 and GSE42830 were retrieved from publicly available gene expression omnibus (GEO) database. Deregulated genes (DEGs) were identified using GEO2R online tool and Gene Ontology (GO), protein-protein interaction (PPI) network analysis was performed using Metascape and STRING databases. Significant genes (n = 8) were identified using T-test/ANOVA and Molecular Complex Detection (MCODE) score ≥10, which was validated in GSE34608 dataset. The diagnostic potential of three biomarkers was assessed using Area Under Curve (AUC) of Receiver Operating Characteristic (ROC) plot. The transcriptional levels of these genes were also examined in a separate dataset GSE31348, to monitor the patterns of variation during tuberculosis treatment., Results: A total of 62 common DEGs (57 upregulated, 7 downregulated genes) were identified in two discovery datasets. GO functions and pathway enrichment analysis shed light on the functional roles of these DEGs in immune response and type-II interferon signaling. The genes in Module-1 (n = 18) were linked to innate immune response, interferon-gamma signaling. The common genes (n = 8) were validated in GSE34608 dataset, that corroborates the results obtained from discovery sets. The gene expression levels demonstrated responsiveness to Mtb infection during anti-TB therapy in GSE31348 dataset. In GSE34608 dataset, the expression levels of three specific genes, GBP5, IFITM3, and EPSTI1, emerged as potential diagnostic makers. In combination, these genes scored remarkable diagnostic performance with 100% sensitivity and 89% specificity, resulting in an impressive Area Under Curve (AUC) of 0.958. However, GBP5 alone showed the highest AUC of 0.986 with 100% sensitivity and 89% specificity., Conclusions: The study presents valuable insights into the critical gene network perturbed during tuberculosis. These genes are determinants for assessing the effectiveness of an anti-TB response and distinguishing between active TB and healthy individuals. GBP5, IFITM3 and EPSTI1 emerged as candidate core genes in TB and holds potential as novel molecular targets for the development of interventions in the treatment of TB., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Arya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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12. Lower Microscopy Sensitivity with Decreasing Malaria Prevalence in the Urban Amazon Region, Brazil, 2018-2021.
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Rodrigues PT, Johansen IC, Ladeia WA, Esquivel FD, Corder RM, Tonini J, Calil PR, Fernandes ARJ, Fontoura PS, Cavasini CE, Vinetz JM, Castro MC, and Ferreira MU
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- Brazil epidemiology, Humans, Prevalence, Female, Male, Adult, Adolescent, Malaria, Vivax epidemiology, Malaria, Vivax parasitology, Child, Malaria, Falciparum epidemiology, Malaria, Falciparum parasitology, Malaria, Falciparum prevention & control, Malaria epidemiology, Malaria transmission, Malaria prevention & control, Malaria parasitology, Plasmodium vivax genetics, Urban Population, Child, Preschool, Plasmodium falciparum genetics, Middle Aged, Young Adult, Infant, History, 21st Century, Microscopy methods
- Abstract
Malaria is increasingly diagnosed in urban centers across the Amazon Basin. In this study, we combined repeated prevalence surveys over a 4-year period of a household-based random sample of 2,774 persons with parasite genotyping to investigate the epidemiology of malaria in Mâncio Lima, the main urban transmission hotspot in Amazonian Brazil. We found that most malarial infections were asymptomatic and undetected by point-of-care microscopy. Our findings indicate that as malaria transmission decreases, the detection threshold of microscopy rises, resulting in more missed infections despite similar parasite densities estimated by molecular methods. We identified genetically highly diverse populations of Plasmodium vivax and P. falciparum in the region; occasional shared lineages between urban and rural residents suggest cross-boundary propagation. The prevalence of low-density and asymptomatic infections poses a significant challenge for routine surveillance and the effectiveness of malaria control and elimination strategies in urbanized areas with readily accessible laboratory facilities.
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- 2024
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13. Effect of spatiotemporal variables on abundance, biting activity and parity of Nyssorhynchus darlingi (Diptera: Culicidae) in peri-Iquitos, Peru.
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Bickersmith SA, Saavedra MP, Prussing C, Lange RE, Morales JA, Alava F, Vinetz JM, Gamboa D, Moreno M, and Conn JE
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- Animals, Female, Humans, Peru epidemiology, Mosquito Vectors, Seasons, Anopheles genetics, Malaria epidemiology, Malaria, Vivax epidemiology, Bites and Stings, Malaria, Falciparum, Plasmodium
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Background: In malaria endemic regions of the Peruvian Amazon, rainfall together with river level and breeding site availability drive fluctuating vector mosquito abundance and human malaria cases, leading to temporal heterogeneity. The main variables influencing spatial transmission include location of communities, mosquito behaviour, land use/land cover, and human ecology/behaviour. The main objective was to evaluate seasonal and microgeographic biting behaviour of the malaria vector Nyssorhynchus (or Anopheles) darlingi in Amazonian Peru and to investigate effects of seasonality on malaria transmission., Methods: We captured mosquitoes from 18:00 to 06:00 h using Human Landing Catch in two riverine (Lupuna, Santa Emilia) and two highway (El Triunfo, Nuevo Horizonte) communities indoors and outdoors from 8 houses per community, during the dry and rainy seasons from February 2016 to January 2017. We then estimated parity rate, daily survival and age of a portion of each collection of Ny. darlingi. All collected specimens of Ny. darlingi were tested for the presence of Plasmodium vivax or Plasmodium falciparum sporozoites using real-time PCR targeting the small subunit of the 18S rRNA., Results: Abundance of Ny. darlingi varied across village, season, and biting behaviour (indoor vs outdoor), and was highly significant between rainy and dry seasons (p < 0.0001). Biting patterns differed, although not significantly, and persisted regardless of season, with peaks in highway communities at ~ 20:00 h in contrast to biting throughout the night (i.e., 18:00-06:00) in riverine communities. Of 3721 Ny. darlingi tested for Plasmodium, 23 (0.62%) were infected. We detected Plasmodium-infected Ny. darlingi in both community types and most (20/23) were captured outdoors during the rainy season; 17/23 before midnight. Seventeen Ny. darlingi were infected with P. vivax, and 6 with P. falciparum. No infected Ny. darlingi were captured during the dry season. Significantly higher rates of parity were detected in Ny. darlingi during the rainy season (average 64.69%) versus the dry season (average 36.91%) and by community, Lupuna, a riverine village, had the highest proportion of parous to nulliparous females during the rainy season., Conclusions: These data add a seasonal dimension to malaria transmission in peri-Iquitos, providing more evidence that, at least locally, the greatest risk of malaria transmission is outdoors during the rainy season mainly before midnight, irrespective of whether the community was located adjacent to the highway or along the river., (© 2024. The Author(s).)
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- 2024
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14. Case Report: Plasmodium vivax Sporozoite Melanization in the Midgut and Salivary Gland of the Malaria Vector Anopheles darlingi.
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Dos Santos NAC, Bastos ADS, Araújo JE, Pontual JDC, Medeiros JF, Vinetz JM, and Araujo MDS
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- Animals, Humans, Plasmodium vivax, Sporozoites, Mosquito Vectors parasitology, Salivary Glands, Malaria, Anopheles parasitology, Malaria, Vivax
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Anopheles darlingi is the primary malaria vector in the Amazon region and is highly susceptible to both Plasmodium vivax and Plasmodium falciparum parasites. Although anopheline mosquitoes may develop melanotic encapsulation in response to Plasmodium parasites, there is no record of An. darlingi exhibiting a melanization response to P. vivax, the main malaria parasite in the Americas. Here, we report the occurrence of P. vivax sporozoite melanization in An. darlingi mosquitoes.
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- 2024
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15. A prospective cohort study linking migration, climate, and malaria risk in the Peruvian Amazon - CORRIGENDUM.
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Gunderson AK, Recalde-Coronel C, Zaitchik BF, Yori PP, Rengifo Pinedo S, Paredes Olortegui M, Kosek M, Vinetz JM, and Pan WK
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- Humans, Prospective Studies, Peru epidemiology, Malaria epidemiology, Malaria, Falciparum, Malaria, Vivax
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- 2024
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16. Production and Purification of Cysteine-Rich Leptospiral Virulence-Modifying Proteins with or Without mCherry Fusion.
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Chaurasia R, Liang C, How K, Vieira DS, and Vinetz JM
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Recombinant fluorescent fusion proteins are fundamental to advancing many aspects of protein science. Such proteins are typically used to enable the visualization of functional proteins in experimental systems, particularly cell biology. An important problem in biotechnology is the production of functional, soluble proteins. Here we report the use of mCherry-fusions of soluble, cysteine-rich, Leptospira-secreted exotoxins in the PF07598 gene family, the so-called virulence modifying (VM) proteins. The mCherry fusion proteins facilitated the visual detection of pink colonies of the VM proteins (LA3490 and LA1402) and following them through lysis and sequential chromatography steps. CD-spectroscopy analysis confirmed the stability and robustness of the mCherry-fusion protein, with a structure comparable to AlphaFold structural predictions. LA0591, a unique member of the PF07598 gene family that lacks N-terminal ricin B-like domains, was produced without mCherry tag that strengthens the recombinant protein production protocol without fusion protein as well. The current study provides the approaches for the synthesis of 50-125 kDa soluble, cysteine-rich, high-quality fast protein liquid chromatography (FPLC)-purified protein, with and without a mCherry tag. The use of mCherry-fusion proteins enables a streamlined, efficient process of protein production and qualitative and quantitative downstream analytical and functional studies. Approaches for troubleshooting and optimization were evaluated to overcome difficulties in recombinant protein expression and purification, demonstrating biotechnology utility in accelerating recombinant protein production., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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17. A prospective cohort study linking migration, climate, and malaria risk in the Peruvian Amazon.
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Gunderson AK, Recalde-Coronel C, Zaitchick BF, Yori PP, Rengifo Pinedo S, Paredes Olortegui M, Kosek M, Vinetz JM, and Pan WK
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- Humans, Plasmodium vivax, Plasmodium falciparum, Peru epidemiology, Prospective Studies, Malaria, Vivax epidemiology, Malaria, Falciparum epidemiology, Malaria epidemiology
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Migration is an important risk factor for malaria transmission for malaria transmission, creating networks that connect Plasmodium between communities. This study aims to understand the timing of why people in the Peruvian Amazon migrated and how characteristics of these migrants are associated with malaria risk. A cohort of 2,202 participants was followed for three years (July 2006 - October 2009), with thrice-weekly active surveillance to record infection and recent travel, which included travel destination(s) and duration away. Migration occurred more frequently in the dry season, but the 7-day rolling mean (7DRM) streamflow was positively correlated with migration events (OR 1.25 (95% CI: 1.138, 1.368)). High-frequency and low-frequency migrant populations reported 9.7 (IRR 7.59 (95% CI:.381, 13.160)) and 4.1 (IRR 2.89 (95% CI: 1.636, 5.099)) times more P. vivax cases than those considered non-migrants and 30.7 (IRR 32.42 (95% CI: 7.977, 131.765)) and 7.4 (IRR 7.44 (95% CI: 1.783, 31.066)) times more P. falciparum cases, respectively. High-frequency migrants employed in manual labour within their community were at 2.45 (95% CI: 1.113, 5.416) times higher risk than non-employed low-frequency migrants. This study confirms the importance of migration for malaria risk as well as factors increasing risk among the migratory community, including, sex, occupation, and educational status.
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- 2023
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18. Whole genome sequencing data of Leptospira weilii and Leptospira kirschneri isolated from human subjects of Sri Lanka.
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Senavirathna I, Jayasundara D, Warnasekara J, Matthias MA, Vinetz JM, and Agampodi S
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Leptospirosis is a re-emerging zoonotic disease. This article reports the complete genome sequences of three novel strains of Genus Leptospira : two from the species Leptospira weilii (FMAS_RT1, FMAS_PD2) and one from Leptospira kirschneri (FMAS_PN5). These isolates were recovered from the blood samples of acute febrile patients in different geographical and climatic zones of Sri Lanka. High-quality genomic DNA was extracted from the three isolates in mid-log phase cultures. Whole genome sequencing was conducted using the PacBio Single Molecule Real-Time (SMRT) platform to identify the species, genome features, and novelty of the strains. The annotation was conducted using RAST (Rapid Annotation Using Subsystem Technology version 2.0) and the NCBI Prokaryotic Genome Annotation Pipeline. The genome sequences of three isolates have been deposited in the Mendeley data repository and the National Center for Biotechnology Information (NCBI) repository. This data will be useful for future researchers when conducting comparative genomic analysis, revealing the exact mechanism of pathogenesis of leptospirosis and developing molecular diagnostic tools for early detection., (© 2023 The Author(s).)
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- 2023
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19. Differences in Mortality Among Patients With Asthma and COPD Hospitalized With COVID-19.
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Liu Y, Rajeevan H, Simonov M, Lee S, Wilson FP, Desir GV, Vinetz JM, Yan X, Wang Z, Clark BJ, Possick JD, Price C, Lutchmansingh DD, Ortega H, Zaeh S, Gomez JV, Cohn L, Gautam S, and Chupp GL
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- Humans, Retrospective Studies, Inflammation, COVID-19 complications, Pulmonary Disease, Chronic Obstructive diagnosis, Asthma diagnosis, Eosinophilia complications, Diabetes Mellitus, Type 2
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Background: It remains unclear whether patients with asthma and/or chronic obstructive pulmonary disease (COPD) are at increased risk for severe coronavirus disease 2019 (COVID-19)., Objective: Compare in-hospital COVID-19 outcomes among patients with asthma, COPD, and no airway disease., Methods: A retrospective cohort study was conducted on 8,395 patients admitted with COVID-19 between March 2020 and April 2021. Airway disease diagnoses were defined using International Classification of Diseases, 10
th Revision codes. Mortality and sequential organ failure assessment (SOFA) scores were compared among groups. Logistic regression analysis was used to identify and adjust for confounding clinical features associated with mortality., Results: The median SOFA score in patients without airway disease was 0.32 and mortality was 11%. In comparison, asthma patients had lower SOFA scores (median 0.15; P < .01) and decreased mortality, even after adjusting for age, diabetes, and other confounders (odds ratio 0.65; P = .01). Patients with COPD had higher SOFA scores (median 0.86; P < .01) and increased adjusted odds of mortality (odds ratio 1.40; P < .01). Blood eosinophil count of 200 cells/μL or greater, a marker of type 2 inflammation, was associated with lower mortality across all groups. Importantly, patients with asthma showed improved outcomes even after adjusting for eosinophilia, indicating that noneosinophilic asthma was associated with protection as well., Conclusions: COVID-19 severity was increased in patients with COPD and decreased in those with asthma, eosinophilia, and noneosinophilic asthma, independent of clinical confounders. These findings suggest that COVID-19 severity may be influenced by intrinsic immunological factors in patients with airway diseases, such as type 2 inflammation., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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20. Optimization of Plasmodium vivax infection of colonized Amazonian Anopheles darlingi.
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Andrade AO, Santos NAC, Bastos AS, Pontual JDC, Araújo CS, Lima AS, Martinez LN, Ferreira AS, Aguiar ACC, Teles CBG, Guido RVC, Santana RA, Lopes SCP, Medeiros JF, Rizopoulos Z, Vinetz JM, Campo B, Lacerda MVG, and Araújo MS
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- Animals, Humans, Female, Plasmodium vivax, Sporozoites, Hepatocytes, Anopheles parasitology, Malaria, Vivax parasitology
- Abstract
Obtaining Plasmodium vivax sporozoites is essential for in vitro culture of liver stage parasites, not only to understand fundamental aspects of parasite biology, but also for drug and vaccine development. A major impediment to establish high-throughput in vitro P. vivax liver stage assays for drug development is obtaining sufficient numbers of sporozoites. To do so, female anopheline mosquitoes have to be fed on blood from P. vivax-infected patients through an artificial membrane-feeding system, which in turns requires a well-established Anopheles colony. In this study we established conditions to provide a robust supply of P. vivax sporozoites. Adding a combination of serum replacement and antibiotics to the membrane-feeding protocol was found to best improve sporozoite production. A simple centrifugation method appears to be a possible tool for rapidly obtaining purified sporozoites with a minimal loss of yield. However, this method needs to be better defined since sporozoite viability and hepatocyte infection were not evaluated., (© 2023. Springer Nature Limited.)
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- 2023
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21. Mutations Linked to Insecticide Resistance Not Detected in the Ace-1 or VGSC Genes in Nyssorhynchus darlingi from Multiple Localities in Amazonian Brazil and Peru.
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Bickersmith SA, Jurczynski JD, Sallum MAM, Chaves LSM, Bergo ES, Rodriguez GAD, Morante CA, Rios CT, Saavedra MP, Alava F, Gamboa D, Vinetz JM, and Conn JE
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- Animals, Acetylcholinesterase genetics, Insecticide Resistance genetics, Brazil, Peru epidemiology, Mosquito Vectors genetics, Mutation, Codon, Malaria, Anopheles genetics, Insecticides pharmacology, Pyrethrins pharmacology, Voltage-Gated Sodium Channels genetics
- Abstract
Indoor residual spray (IRS), mainly employing pyrethroid insecticides, is the most common intervention for preventing malaria transmission in many regions of Latin America; the use of long-lasting insecticidal nets (LLINs) has been more limited. Knockdown resistance ( kdr ) is a well-characterized target-site resistance mechanism associated with pyrethroid and DDT resistance. Most mutations detected in acetylcholinesterase-1 ( Ace-1 ) and voltage-gated sodium channel ( VGSC ) genes are non-synonymous, resulting in a change in amino acid, leading to the non-binding of the insecticide. In the present study, we analyzed target-site resistance in Nyssorhynchus darlingi , the primary malaria vector in the Amazon, in multiple malaria endemic localities. We screened 988 wild-caught specimens of Ny. darlingi from three localities in Amazonian Peru and four in Amazonian Brazil. Collections were conducted between 2014 and 2021. The criteria were Amazonian localities with a recent history as malaria hotspots, primary transmission by Ny. darlingi , and the use of both IRS and LLINs as interventions. Fragments of Ace-1 (456 bp) and VGSC (228 bp) were amplified, sequenced, and aligned with Ny. darlingi sequences available in GenBank. We detected only synonymous mutations in the frequently reported Ace-1 codon 280 known to confer resistance to organophosphates and carbamates, but detected three non-synonymous mutations in other regions of the gene. Similarly, no mutations linked to insecticide resistance were detected in the frequently reported codon (995) at the S6 segment of domain II of VGSC . The lack of genotypic detection of insecticide resistance mutations by sequencing the Ace-1 and VGSC genes from multiple Ny. darlingi populations in Brazil and Peru could be associated with low-intensity resistance, or possibly the main resistance mechanism is metabolic.
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- 2023
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22. Complete genome sequences of twelve strains of Leptospira interrogans isolated from humans in Sri Lanka.
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Senavirathna I, Jayasundara D, Warnasekara J, Matthias MA, Vinetz JM, and Agampodi S
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- Humans, Animals, Phylogeny, Sri Lanka, Serogroup, Zoonoses, Leptospira interrogans genetics, Leptospirosis, Leptospira genetics
- Abstract
Leptospirosis, a major zoonotic disease caused by pathogenic Leptospira spp. is recognized globally as an emerging zoonotic disease. Whole-genome sequencing reveals hidden messages about Leptospira's pathogenesis. We used Single Molecule Real-Time (SMRT) sequencing to obtain complete genome sequences of twelve L. interrogans isolates from febrile patients from Sri Lanka for a comparative whole genome sequencing study. The sequence data generated 12 genomes with a coverage greater than X600 with sizes ranging from 4.62 Mb to 5.16 Mb, and a G + C content ranging from 35.00% to 35.42%. The total number of coding sequences predicted by the NCBI (National Center for Biotechnology Information) genome assembly platform ranged from 3845 to 4621 for the twelve strains. Leptospira serogroup with similar-sized LPS biosynthetic loci that belonged to the same clade had a close relationship in the phylogenetic analysis. Nonetheless, variations in the genes encoding sugar biosynthesis were found in the serovar determinant region (rfb locus). Type I and Type III CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) systems were found in all of the strains. Genome BLAST Distance Phylogeny of these sequences allowed for detailed genomic strain typing. These findings may help us better understand the pathogenesis, develop a tools for early diagnosis, comparative genomic analysis and evolution of Leptospira., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Published by Elsevier B.V.)
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- 2023
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23. Natural Infection of Nyssorhynchus darlingi and Nyssorhynchus benarrochi B with Plasmodium during the Dry Season in the Understudied Low-Transmission Setting of Datem del Marañon Province, Amazonian Peru.
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Conn JE, Bickersmith SA, Saavedra MP, Morales JA, Alava F, Diaz Rodriguez GA, Del Aguila Morante CR, Tong CG, Alvarez-Antonio C, Daza Huanahui JM, Vinetz JM, and Gamboa D
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- Animals, Humans, Peru epidemiology, Seasons, Anopheles parasitology, Plasmodium, Malaria epidemiology
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The persistence of malaria hotspots in Datem del Marañon Province, Peru, prompted vector control units at the Ministry of Health, Loreto Department, to collaborate with the Amazonian International Center of Excellence for Malaria Research to identify the main vectors in several riverine villages that had annual parasite indices > 15 in 2018-2019. Anophelinae were collected indoors and outdoors for two 12-hour nights/community during the dry season in 2019 using human landing catch. We identified four species: Nyssorhynchus benarrochi B, Nyssorhynchus darlingi, Nyssorhynchus triannulatus, and Anopheles mattogrossensis. The most abundant, Ny. benarrochi B, accounted for 96.3% of the total (7,550/7,844), of which 61.5% were captured outdoors (4,641/7,550). Six mosquitoes, one Ny. benarrochi B and five Ny. darlingi, were infected by Plasmodium falciparum or Plasmodium vivax. Human biting rates ranged from 0.5 to 592.8 bites per person per hour for Ny. benarrochi B and from 0.5 to 32.0 for Ny. darlingi, with entomological inoculation rates as high as 0.50 infective bites per night for Ny. darlingi and 0.25 for Ny. benarrochi B. These data demonstrate the risk of malaria transmission by both species even during the dry season in villages in multiple watersheds in Datem del Marañon province.
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- 2023
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24. Transmission-blocking activity of antimalarials for Plasmodium vivax malaria in Anopheles darlingi.
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Andrade AO, Santos NAC, Bastos AS, Pontual JDC, Araújo JE, Silva AMV, Martinez LN, Lima AA, Aguiar ACC, G Teles CB, Medeiros JF, Pereira DB, Vinetz JM, Gazzinelli RT, and Araújo MS
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- Animals, Humans, Primaquine pharmacology, Primaquine therapeutic use, Chloroquine pharmacology, Chloroquine therapeutic use, Plasmodium vivax, Antimalarials pharmacology, Antimalarials therapeutic use, Malaria, Vivax drug therapy, Malaria, Vivax parasitology, Anopheles parasitology, Malaria drug therapy
- Abstract
Malaria is caused by parasite of the genus Plasmodium and is still one of the most important infectious diseases in the world. Several biological characteristics of Plasmodium vivax contribute to the resilience of this species, including early gametocyte production, both of which lead to efficient malaria transmission to mosquitoes. This study evaluated the impact of currently used drugs on the transmission of P. vivax. Participants received one of the following treatments for malaria: i) chloroquine [10 mg/kg on day 1 and 7.5 mg/kg on day 2 and 3] co-administered with Primaquine [0.5 mg/kg/day for 7 days]; ii) Chloroquine [10 mg/kg on day 1 and 7.5 mg/kg on day 2 and 3] co-administered with one-dose of Tafenoquine [300 mg on day 1]; and iii) Artesunate and Mefloquine [100 mg and 200 mg on day 1, 2 and 3] co-administered with Primaquine [0.5 mg/kg/day for 14 days]. Patient blood was collected before treatment and 4 h, 24 h, 48 h and 72 h after treatment. The blood was used to perform a direct membrane feeding assay (DMFA) using Anopheles darlingi mosquitoes. The results showed 100% inhibition of the mosquito infection after 4 h using ASMQ+PQ, after 24 h for the combination of CQ+PQ and 48 h using CQ+TQ. The density of gametocytes declined over time in all treatment groups, although the decline was more rapid in the ASMQ+PQ group. In conclusion, it was possible to demonstrate the transmission-blocking efficacy of the malaria vivax treatment and that ASMQ+PQ acts faster than the two other treatments., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)
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- 2023
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25. mCherry Fusion Proteins Facilitate Production of Recombinant, Cysteine-Rich Leptospira interrogans Proteins in Escherichia coli .
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Chaurasia R, Liang C, How K, Vieira DS, and Vinetz JM
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Background: Recombinant fluorescent fusion proteins are fundamental to advancing many aspects of protein science. Such proteins are typically used to enable the visualization of functional proteins in experimental systems, particularly cell biology. An important problem in biotechnology is the production of functional, soluble proteins. Here we report the use of mCherry-fusions of soluble, cysteine-rich, Leptospira -secreted exotoxins in the PF07598 gene family, the so-called virulence modifying (VM) proteins., Results: The mCherry fusion proteins facilitated the production of the VM proteins (LA3490 and LA1402) by enabling the visual detection of pink colonies and following them through lysis and sequential chromatography steps. CD-spectroscopy analysis confirmed the stability and robustness of the mCherry-fusion protein, with a structure comparable to AlphaFold structural predictions. LA0591, a unique member of the PF07598 gene family that lacks N-terminal ricin B-like domains, was produced as a tagless protein that strengthens the recombinant protein production protocol. The current study provides the approaches for the synthesis of 50-125 kDa soluble, cysteine-rich, high-quality mCherry tagged or tagless fast protein liquid chromatography (FPLC)-purified protein., Conclusions: The use of mCherry-fusion proteins enables a streamlined, efficient process of protein production and qualitative and quantitative downstream analytical and functional studies. Approaches for troubleshooting and optimization were systemically evaluated to overcome difficulties in recombinant protein expression and purification, demonstrating biotechnology utility in accelerating recombinant protein production., Competing Interests: Conflicts of interest Authors RC, CL, KH, DSV, and JMV declare that they have no conflict of interest regarding the publication of this work.
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- 2023
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26. In silico prediction of molecular mechanisms of toxicity mediated by the leptospiral PF07598 gene family-encoded virulence-modifying proteins.
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Chaurasia R and Vinetz JM
- Abstract
Mechanisms of leptospirosis pathogenesis remain unclear despite the identification of a number of potential leptospiral virulence factors. We recently demonstrated potential mechanisms by which the virulence-modifying (VM) proteins-defined as containing a Domain of Unknown function (DUF1561), encoded by the PF07598 gene family-found only in group 1 pathogenic Leptospira -might mediate the clinical pathogenesis of leptospirosis. VM proteins belongs to classical AB toxin paradigm though have a unique AB domain architecture, unlike other AB toxins such as diphtheria toxin, pertussis toxin, shiga toxin, or ricin toxin which are typically encoded by two or more genes and self-assembled into a multi-domain holotoxin. Leptospiral VM proteins are secreted R-type lectin domain-containing exotoxins with discrete N-terminal ricin B-like domains involved in host cell surface binding, and a C-terminal DNase/toxin domain. Here we use the artificial intelligence-based AlphaFold algorithm and other computational tools to predict and elaborate on details of the VM protein structure-function relationship. Comparative AlphaFold and CD-spectroscopy defined the consistent secondary structure (Helix and ß-sheet) content, and the stability of the functional domains were further supported by molecular dynamics simulation. VM proteins comprises distinctive lectic family (QxW)
3 motifs, the Mycoplasma CARDS toxin (D3 domain, aromatic patches), C-terminal similarity with mammalian DNase I. In-silico study proposed that Gln412, Gln523, His533, Thr59 are the high binding energy or ligand binding residues plausibly anticipates in the functional activities. Divalent cation (Mg+2 -Gln412) and phosphate ion (PO4 ]-3 -Arg615) interaction further supports the functional activities driven by C-terminal domain. Computation-driven structure-function studies of VM proteins will guide experimentation towards mechanistic understandings of leptospirosis pathogenesis, which underlie development of new therapeutic and preventive measures for this devastating disease., Competing Interests: JV and spouse have an equity interest in LeptoX, which may have a future interest in licensing this work. The work reported here has been filed in patent applications from Yale University., (Copyright © 2023 Chaurasia and Vinetz.)- Published
- 2023
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27. Comparison of the PF07598-Encoded Virulence-Modifying Proteins of L. interrogans and L. borgpetersenii .
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Vieira DS, Chaurasia R, and Vinetz JM
- Abstract
Leptospirosis is an emerging infectious disease, with increasing frequency and severity of outbreaks, a changing epidemiology of populations at risk, and the emergence of new strains, serovars, serogroups, and species. Virulence-modifying (VM) proteins encoded by the PF07598 gene family are hypothesized to be Leptospira -secreted exotoxins that mediate the molecular and cellular pathogenesis of severe and fatal leptospirosis. If confirmed experimentally, this concept could revolutionize the treatment, diagnosis, prognosis, and vaccine-mediated prevention of leptospirosis by enabling a novel array of targeted interventions. VM proteins, as with other bacterial-secreted protein exotoxins, mediate their virulence effects by attaching to eukaryotic cells, competing with other microorganisms for limited resources in environmental niches, directly intoxicating target cells, and disrupting their function in the mammalian host. In contrast with the most pathogenic group of Lept ospira , particularly L. interrogans , whose genomes contain 12-15 PF07598 paralogs, strains of the livestock and human pathogen L. borgpetersenii have two PF07598 paralogs. Given the possible non-environmentally mediated transmission of some L. borgpetersenii strains and the much smaller number of VM proteins in this species, their role in infection and disease may well differ from other leptospiral species. Comparison of VM proteins from different clades of pathogenic Leptospira may deepen our understanding of leptospirosis's pathogenesis, leading to novel approaches to ameliorating Leptospira infection in humans and animals.
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- 2022
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28. Culture-Independent Detection and Identification of Leptospira Serovars.
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Matthias MA, Lubar AA, Lanka Acharige SS, Chaiboonma KL, Pilau NN, Marroquin AS, Jayasundara D, Agampodi S, and Vinetz JM
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- Humans, Animals, Dogs, Serogroup, Prospective Studies, Serum, Leptospira genetics, Leptospirosis diagnosis, Leptospirosis veterinary
- Abstract
Pathogenic Leptospira , the causative agents of leptospirosis, comprise >200 serotypes (called serovars). Most have a restricted reservoir-host range, and some, e.g., serovar Copenhageni, are cosmopolitan and of public health importance owing to their propensity to produce severe, fatal disease in humans. Available serotyping approaches-such as multilocus sequence typing, core genome sequence typing, pulsed-field gel electrophoresis, and the cross-agglutination absorption test-are tedious and expensive, and require isolation of the organisms in culture media-a protracted and incredibly inefficient process-precluding their use in prospective studies or outbreak investigations. The unavailability of culture-independent assays capable of distinguishing Leptospira serotypes remains a crucial gap in the field. Here, we have developed a simple yet specific real-time qPCR assay-targeting a Leptospira -unique gene encoding a putative polysaccharide flippase-that provides intraspecies, serotype-defining (i.e., epidemiologically useful) information, and improves upon the sensitivity of preferred lipL32 -based qPCR-based diagnostic tests. The assay, dubbed RAgI ("rage one"), is r apid and a ffordable, and reliably and specifically detects g roup I pathogenic Leptospira in culture, serum, and urine, with no detectable off-target amplification-even of the genetically related but low virulence group II pathogenic (formerly "intermediate") or nonpathogenic Leptospira . It retained 100% diagnostic specificity when tested against difficult sample types, including field-collected dog urine samples and environmental samples containing varied and complex microbial species-consortia. This assay holds considerable promise in the clinical setting, and for routine epidemiological and environmental surveillance studies. IMPORTANCE Leptospirosis is caused by a diverse group of pathogenic spirochetes comprising over 200 different serotypes. Some are widely reported and of public health importance owing to their propensity to produce severe, fatal disease in humans. Apart from their tedium and expense, current serotyping approaches require isolation of the organisms in culture media-a protracted and incredibly inefficient process-rendering them useless clinically and limiting their utilization in prospective studies or outbreak investigations. The unavailability of culture-independent assays capable of distinguishing Leptospira serotypes remains a crucial gap in the field. The 11108 qPCR-assay overcomes this barrier to progress via direct taxonomic and serotype classification of Leptospira from urine and serum samples, and hence, is the first qPCR-based prognostic test for human leptospirosis.
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- 2022
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29. Effect of out-of-village working activities on recent malaria exposure in the Peruvian Amazon using parametric g-formula.
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Carrasco-Escobar G, Rosado J, Nolasco O, White MT, Mueller I, Castro MC, Rodriguez-Ferruci H, Gamboa D, Llanos-Cuentas A, Vinetz JM, and Benmarhnia T
- Subjects
- Adult, Male, Female, Humans, Plasmodium falciparum, Peru epidemiology, Seroepidemiologic Studies, Cross-Sectional Studies, Malaria, Falciparum parasitology, Malaria epidemiology
- Abstract
In the Amazon Region of Peru, occupational activities are important drivers of human mobility and may increase the individual risk of being infected while contributing to increasing malaria community-level transmission. Even though out-of-village working activities and other mobility patterns have been identified as determinants of malaria transmission, no studies have quantified the effect of out-of-village working activities on recent malaria exposure and proposed plausible intervention scenarios. Using two population-based cross-sectional studies in the Loreto Department in Peru, and the parametric g-formula method, we simulated various hypothetical scenarios intervening in out-of-village working activities to reflect their potential health benefits. This study estimated that the standardized mean outcome (malaria seroprevalence) in the unexposed population (no out-of-village workers) was 44.6% (95% CI: 41.7%-47.5%) and 66.7% (95% CI: 61.6%-71.8%) in the exposed population resulting in a risk difference of 22.1% (95% CI: 16.3%-27.9%). However, heterogeneous patterns in the effects of interest were observed between peri-urban and rural areas (Cochran's Q test = 15.5, p < 0.001). Heterogeneous patterns were also observed in scenarios of increased prevalence of out-of-village working activities and restriction scenarios by gender (male vs. female) and age (18 and under vs. 19 and older) that inform possible occupational interventions targetting population subgroups. The findings of this study support the hypothesis that targeting out-of-village workers will considerably benefit current malaria elimination strategies in the Amazon Region. Particularly, males and adult populations that carried out out-of-village working activities in rural areas contribute the most to the malaria seropositivity (recent exposure to the parasite) in the Peruvian Amazon., (© 2022. The Author(s).)
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- 2022
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30. Evidence-Based Malaria Control and Elimination in the Amazon: Input from the International Center of Excellence in Malaria Research Network in Peru and Brazil.
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Ferreira MU, Gamboa D, Torres K, Rodriguez-Ferrucci H, Soto-Calle VE, Pardo K, Fontoura PS, Tomko SS, Gazzinelli RT, Conn JE, Castro MC, Llanos-Cuentas A, and Vinetz JM
- Subjects
- Animals, Brazil epidemiology, Humans, Mosquito Vectors parasitology, Peru epidemiology, Anopheles parasitology, Malaria epidemiology, Malaria prevention & control
- Abstract
Malaria remains endemic in 17 countries in the Americas, where 723,000 cases were reported in 2019. The majority (> 90%) of the regional malaria burden is found within the Amazon Basin, which includes nine countries and territories in South America. Locally generated evidence is critical to provide information to public health decision makers upon which the design of efficient and regionally directed malaria control and elimination programs can be built. Plasmodium vivax is the predominant malaria parasite in the Amazon Basin. This parasite species appears to be more resilient to malaria control strategies worldwide. Asymptomatic Plasmodium infections constitute a potentially infectious reservoir that is typically missed by routine microscopy-based surveillance and often remains untreated. The primary Amazonian malaria vector, Nyssorhynchus (formerly Anopheles) darlingi, has changed its behavior to feed and rest predominantly outdoors, reducing the efficiency of core vector control measures such as indoor residual spraying and distribution of long-lasting insecticide-treated bed nets. We review public health implications of recent field-based research carried out by the Amazonia International Center of Excellence in Malaria Research in Peru and Brazil. We discuss the relative role of traditional and novel tools and strategies for better malaria control and elimination across the Amazon, including improved diagnostic methods, new anti-relapse medicines, and biological larvicides, and emphasize the need to integrate research and public health policymaking.
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- 2022
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31. Malaria Resilience in South America: Epidemiology, Vector Biology, and Immunology Insights from the Amazonian International Center of Excellence in Malaria Research Network in Peru and Brazil.
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Torres K, Ferreira MU, Castro MC, Escalante AA, Conn JE, Villasis E, da Silva Araujo M, Almeida G, Rodrigues PT, Corder RM, Fernandes ARJ, Calil PR, Ladeia WA, Garcia-Castillo SS, Gomez J, do Valle Antonelli LR, Gazzinelli RT, Golenbock DT, Llanos-Cuentas A, Gamboa D, and Vinetz JM
- Subjects
- Animals, Biology, Brazil epidemiology, Humans, Mosquito Vectors physiology, Peru epidemiology, Anopheles physiology, Malaria epidemiology, Malaria prevention & control
- Abstract
The 1990s saw the rapid reemergence of malaria in Amazonia, where it remains an important public health priority in South America. The Amazonian International Center of Excellence in Malaria Research (ICEMR) was designed to take a multidisciplinary approach toward identifying novel malaria control and elimination strategies. Based on geographically and epidemiologically distinct sites in the Northeastern Peruvian and Western Brazilian Amazon regions, synergistic projects integrate malaria epidemiology, vector biology, and immunology. The Amazonian ICEMR's overarching goal is to understand how human behavior and other sociodemographic features of human reservoirs of transmission-predominantly asymptomatically parasitemic people-interact with the major Amazonian malaria vector, Nyssorhynchus (formerly Anopheles) darlingi, and with human immune responses to maintain malaria resilience and continued endemicity in a hypoendemic setting. Here, we will review Amazonian ICEMR's achievements on the synergies among malaria epidemiology, Plasmodium-vector interactions, and immune response, and how those provide a roadmap for further research, and, most importantly, point toward how to achieve malaria control and elimination in the Americas.
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- 2022
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32. Etiologies of Acute Undifferentiated Febrile Illnesses in and near Iquitos from 1993 to 1999 in the Amazon River Basin of Peru.
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Watts DM, Russell KL, Wooster MT, Sharp TW, Morrison AC, Kochel TJ, Bautista CT, Block K, Guevara C, Aguilar P, Palermo PM, Calampa C, Porter KR, Hayes CG, Weaver SC, de Rosa AT, Vinetz JM, Shope RE, Gotuzzo E, Guzman H, and Tesh RB
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- Humans, Peru epidemiology, Rivers, Fever epidemiology, Encephalitis Virus, Venezuelan Equine, Arboviruses, Leptospirosis epidemiology, Malaria
- Abstract
The objective of this study was to determine the etiology of febrile illnesses among patients from October 1, 1993 through September 30, 1999, in the urban community of Iquitos in the Amazon River Basin of Peru. Epidemiological and clinical data as well as blood samples were obtained from consenting patients at hospitals, health clinics and private residences. Samples were tested for arboviruses in cell cultures and for IgM and IgG antibodies by ELISA. Blood smears were examined for malaria, and sera were tested for antibodies to Leptospira spp. by ELISA and microscopic agglutination. Among 6,607 febrile patients studied, dengue viruses caused 14.6% of the cases, and Venezuelan equine encephalitis virus caused 2.5%, Oropouche virus 1.0%, Mayaro virus 0.4%, and other arboviruses caused 0.2% of the cases. Also, 22.9% of 4,844 patients tested were positive for malaria, and of 400 samples tested, 9% had evidence of acute leptospirosis. Although the study was not designed to assess the importance of these pathogens as a cause of human morbidity in the total population, these results indicate that arboviruses, leptospirosis, and malaria were the cause of approximately 50% of the febrile cases. Although the arboviruses that were diagnosed can produce asymptomatic infections, our findings increased the overall understanding of the relative health burden of these infections, as well as baseline knowledge needed for designing and implementing further studies to better assess the health impact and threat of these pathogens in the Amazon Basin of Peru.
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- 2022
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33. Vaccination With Leptospira interrogans PF07598 Gene Family-Encoded Virulence Modifying Proteins Protects Mice From Severe Leptospirosis and Reduces Bacterial Load in the Liver and Kidney.
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Chaurasia R, Salovey A, Guo X, Desir G, and Vinetz JM
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- Animals, Bacterial Load, Bacterial Vaccines genetics, Escherichia coli genetics, Humans, Kidney pathology, Liver pathology, Mice, Mice, Inbred C3H, Recombinant Proteins genetics, Vaccination, Virulence, Escherichia coli Proteins, Leptospira, Leptospira interrogans, Leptospirosis microbiology
- Abstract
The molecular and cellular pathogenesis of leptospirosis remains poorly understood. Based on comparative bacterial genomics data, we recently identified the hypothetical PF07598 gene family as encoding secreted exotoxins (VM proteins) that mediate cytotoxicity in vitro . To address whether VM proteins mediate in vivo leptospirosis pathogenesis, we tested the hypothesis that VM protein immunization of mice would protect against lethal challenge infection and reduce bacterial load in key target organs. C3H/HeJ mice were immunized with recombinant E. coli- produced, endotoxin-free, leptospiral VM proteins (derived from L. interrogans serovar Lai) in combination with the human-compatible adjuvant, glucopyranoside lipid A/squalene oil-in-water. Mice receiving full length recombinant VM proteins were protected from lethal challenge infection by L. interrogans serovar Canicola and had a 3-4 log
10 reduction in bacterial load in the liver and kidney. These experiments show that immunization with recombinant VM proteins prevents leptospirosis clinical pathogenesis and leads to markedly reduced key target organ infection in this animal model. These data support the role of leptospiral VM proteins as virulence factors and suggest the possibility that a VM protein-based, serovar-independent, pan-leptospirosis vaccine may be feasible., Competing Interests: The work reported here has been filed in patent applications from Yale University. JV and spouse have an equity interest in LeptoX BioPharma, Inc. which may have a future interest in licensing this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chaurasia, Salovey, Guo, Desir and Vinetz.)- Published
- 2022
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34. Insights into Plasmodium vivax Asymptomatic Malaria Infections and Direct Skin-Feeding Assays to Assess Onward Malaria Transmission in the Amazon.
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Moreno M, Torres K, Tong C, García Castillo SS, Carrasco-Escobar G, Guedez G, Torres L, Herrera-Varela M, Guerra L, Guzman-Guzman M, Wong D, Ramirez R, Llanos-Cuentas A, Conn JE, Gamboa D, and Vinetz JM
- Subjects
- Animals, Asymptomatic Infections epidemiology, Cohort Studies, Humans, Mosquito Vectors parasitology, Plasmodium vivax, Anopheles parasitology, Malaria, Malaria, Vivax parasitology
- Abstract
Understanding the reservoir and infectivity of Plasmodium gametocytes to vector mosquitoes is crucial to align strategies aimed at malaria transmission elimination. Yet, experimental information is scarce regarding the infectivity of Plasmodium vivax for mosquitoes in diverse epidemiological settings where the proportion of asymptomatically infected individuals varies at a microgeographic scale. We measured the transmissibility of clinical and subclinical P. vivax malaria parasite carriers to the major mosquito vector in the Amazon Basin, Nyssorhynchus darlingi (formerly Anopheles). A total of 105 participants with natural P. vivax malaria infection were recruited from a cohort study in Loreto Department, Peruvian Amazon. Four of 18 asymptomatic individuals with P. vivax positivity by blood smear infected colony-grown Ny. darlingi (22%), with 2.6% (19 of 728) mosquitoes infected. In contrast, 77% (44/57) of symptomatic participants were infectious to mosquitoes with 51% (890 of 1,753) mosquitoes infected. Infection intensity was greater in symptomatic infections (mean, 17.8 oocysts/mosquito) compared with asymptomatic infections (mean, 0.28 oocysts/mosquito), attributed to parasitemia/gametocytemia level. Paired experiments (N = 27) using direct skin-feeding assays and direct membrane mosquito-feeding assays showed that infectivity to mosquitoes was similar for both methods. Longitudinal studies with longer follow-up of symptomatic and asymptomatic parasite infections are needed to determine the natural variations of disease transmissibility.
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- 2022
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35. Serological and molecular epidemiology of leptospirosis and the role of dogs as sentinel for human infection in Nigeria.
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Pilau NN, Lubar AA, Daneji AI, Mera UM, Magaji AA, Abiayi EA, Chaiboonma KL, Busayo EI, Vinetz JM, and Matthias MA
- Abstract
Objective: Prospective cross-sectional study of dogs in Nigeria to study leptospirosis, inferred to be endemic in all regions of the country by researchers. Aim is to generate empirical updated evidence of leptospiral infection and delineate serovars involved., Methods: Study determined the sero-prevalence and infection rate in 342 dogs using sero-assays, culture isolation and novel qPCR. In-house designed primers targeting conserved regions were used to amplify genes in quantitative Real-Time PCR (qRT-PCR) for leptospiral detection to serogroups. Molecular analysis of the leptospiral 16S rRNA and LipL 32 genes were used for identification of pathogenic Leptospira species. Primers targeting the O-antigen ( rfb ) region of the Leptospira lipopolysaccharide (LPS) were used for differentiating serovars based on comparative melting temperature (T
m ) analysis against reference serogroups., Results: Overall serological and bacteriological prevalence of 56 (16.4%) and 40 (11.7%) respectively was recorded. Vaccination, ages and season(s) were the strongest determinants of infection. Unvaccinated animals, stray dogs and symptomatic dogs presented statistically significant (P < 0.05) higher risk of infection: OR 25.531 (6.108, 106.712; 95% CI)., Discussion: The evidence suggests 1 of every 10 dogs is infected and could be symptomatic for the disease or a carrier of leptospires in the studied region in Nigeria with attendant public health risks., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)- Published
- 2022
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36. Malaria transmission structure in the Peruvian Amazon through antibody signatures to Plasmodium vivax.
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Rosado J, Carrasco-Escobar G, Nolasco O, Garro K, Rodriguez-Ferruci H, Guzman-Guzman M, Llanos-Cuentas A, Vinetz JM, Nekkab N, White MT, Mueller I, and Gamboa D
- Subjects
- Adolescent, Cross-Sectional Studies, Female, Humans, Male, Peru epidemiology, Plasmodium falciparum, Plasmodium vivax, Prevalence, Seroepidemiologic Studies, Malaria, Malaria, Falciparum epidemiology, Malaria, Vivax epidemiology
- Abstract
Background: The landscape of malaria transmission in the Peruvian Amazon is temporally and spatially heterogeneous, presenting different micro-geographies with particular epidemiologies. Most cases are asymptomatic and escape routine malaria surveillance based on light microscopy (LM). Following the implementation of control programs in this region, new approaches to stratify transmission and direct efforts at an individual and community level are needed. Antibody responses to serological exposure markers (SEM) to Plasmodium vivax have proven diagnostic performance to identify people exposed in the previous 9 months., Methodology: We measured antibody responses against 8 SEM to identify recently exposed people and determine the transmission dynamics of P. vivax in peri-urban (Iquitos) and riverine (Mazán) communities of Loreto, communities that have seen significant recent reductions in malaria transmission. Socio-demographic, geo-reference, LM and qPCR diagnosis data were collected from two cross-sectional surveys. Spatial and multilevel analyses were implemented to describe the distribution of seropositive cases and the risk factors associated with exposure to P. vivax., Principal Findings: Low local transmission was detected by qPCR in both Iquitos (5.3%) and Mazán (2.7%); however, seroprevalence indicated a higher level of (past) exposure to P. vivax in Mazán (56.5%) than Iquitos (38.2%). Age and being male were factors associated with high odds of being seropositive in both sites. Higher antibody levels were found in individuals >15 years old. The persistence of long-lived antibodies in these individuals could overestimate the detection of recent exposure. Antibody levels in younger populations (<15 years old) could be a better indicator of recent exposure to P. vivax., Conclusions: The large number of current and past infections detected by SEMs allows for detailed local epidemiological analyses, in contrast to data from qPCR prevalence surveys which did not produce statistically significant associations. Serological surveillance will be increasingly important in the Peruvian Amazon as malaria transmission is reduced by continued control and elimination efforts., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MTW and IM are inventors on patent PCT/US17/67926 on a system, method, apparatus and diagnostic test for Plasmodium vivax. No other authors declare a conflict of interest.
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- 2022
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37. Relative contribution of low-density and asymptomatic infections to Plasmodium vivax transmission in the Amazon: pooled analysis of individual participant data from population-based cross-sectional surveys.
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Ferreira MU, Corder RM, Johansen IC, Kattenberg JH, Moreno M, Rosas-Aguirre A, Ladeia-Andrade S, Conn JE, Llanos-Cuentas A, Gamboa D, Rosanas-Urgell A, and Vinetz JM
- Abstract
Background: Low-density and asymptomatic Plasmodium vivax infections remain largely undetected and untreated and may contribute significantly to malaria transmission in the Amazon., Methods: We analysed individual participant data from population-based surveys that measured P vivax prevalence by microscopy and polymerase chain reaction (PCR) between 2002 and 2015 and modelled the relationship between parasite density and infectiousness to vectors using membrane feeding assay data. We estimated the proportion of sub-patent (i.e., missed by microscopy) and asymptomatic P vivax infections and examined how parasite density relates to clinical manifestations and mosquito infection in Amazonian settings., Findings: We pooled 24,986 observations from six sites in Brazil and Peru. P vivax was detected in 6·8% and 2·1% of them by PCR and microscopy, respectively. 58·5% to 92·6% of P vivax infections were asymptomatic and 61·2% to 96·3% were sub-patent across study sites. P vivax density thresholds associated with clinical symptoms were one order of magnitude higher in children than in adults. We estimate that sub-patent parasite carriers are minimally infectious and contribute 12·7% to 24·9% of the community-wide P vivax transmission, while asymptomatic carriers are the source of 28·2% to 79·2% of mosquito infections., Interpretation: Asymptomatic P vivax carriers constitute a vast infectious reservoir that, if targeted by malaria elimination strategies, could substantially reduce malaria transmission in the Amazon. Infected children may remain asymptomatic despite high parasite densities that elicit clinical manifestations in adults., Funding: US National Institutes of Health, Fundação de Amparo à Pesquisa do Estado de São Paulo, and Belgium Development Cooperation.
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- 2022
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38. Structure-function analysis of cysteine residues in the plasmodium falciparum chitinase, PfCHT1.
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Kaur H, Garber L, Murphy JW, and Vinetz JM
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- Animals, Artificial Intelligence, Chitin metabolism, Cysteine genetics, Disulfides, Escherichia coli genetics, Escherichia coli metabolism, Humans, Mosquito Vectors, Protozoan Proteins, Chitinases chemistry, Plasmodium falciparum genetics
- Abstract
The Plasmodium ookinete uses chitinase activity to penetrate the acellular, chitin-containing peritrophic matrix to invade the mosquito vector. Plasmodium ookinetes from different parasite clades secrete two structurally distinct forms of chitinase, one, a short form lacking a C-terminal putative chitin-binding domain (CBD), the other, a long form with both proenzyme and C-terminal putative chitin-binding domains. Here, we structurally and functionally characterize the three cysteines in the short chitinase of the human-infecting malaria parasite, P. falciparum testing the hypothesis that one unpaired cysteine would not contribute to chitinase-specific enzymatic activity which would identify this residue as potentially involved in intermolecular disulfide bonding and heteromultimeric invasion complex formation as previously described. To test this hypothesis, we produced and characterized recombinant wild-type and cysteine-mutation PfCHT1 proteins in E. coli and used biophysical and enzymatic approaches to examine their enzymatic activities and chitin-binding affinities. The cysteine-203 PfCHT1 mutation had no effect on chitinolytic and chitin-binding functions. The cysteine-220 and cysteine-230 mutants were enzymatically inactive and did not bind to chitin. The artificial intelligence-based protein prediction algorithm, AlphaFold, correctly identified the involvement of cys-220 and cys-230 in the intramolecular disulfide linkages key to maintaining properly folded chitinase structural integrity. AlphaFold predicted that cys-203 cysteine is surface exposed and thus involved in intermolecular protein-protein interaction. Production of the cys-to-ser 203 PfCHT1 mutant facilitated recombinant protein production. Future cellular and biochemical studies are needed to further understand details of Plasmodium ookinete mosquito midgut invasion., (© 2022 The Protein Society.)
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- 2022
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39. Diagnostic method-based underestimation of leptospirosis in clinical and research settings; an experience from a large prospective study in a high endemic setting.
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Warnasekara J, Srimantha S, Kappagoda C, Jayasundara D, Senevirathna I, Matthias M, Agampodi S, and Vinetz JM
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- Agglutination Tests methods, Humans, Prospective Studies, Retrospective Studies, Leptospira genetics, Leptospirosis diagnosis, Leptospirosis epidemiology
- Abstract
Background: Leptospirosis has globally significant human mortality and morbidity, yet estimating the clinical and public health burden of leptospirosis is challenging because timely diagnosis remains limited. The goal of the present study was to evaluate leptospirosis undercounting by current standard methods in both clinical and epidemiological study settings., Methodology/principal Findings: A prospective hospital-based study was conducted in multiple hospitals in Sri Lanka from 2016 to 2019. Culture, whole blood, and urine samples were collected from clinically suspected leptospirosis cases and patients with undifferentiated fever. Analysis of biological samples from 1,734 subjects confirmed 591 (34.1%) cases as leptospirosis and 297 (17.1%) were classified as "probable" leptospirosis cases. Whole blood quantitative PCR (qPCR) did identify the most cases (322/540(60%)) but missed 40%. Cases missed by each method include; urine qPCR, 70% (153/220); acute sample microscopic agglutination test (MAT), 80% (409/510); paired serum sample MAT, 58% (98/170); and surveillance clinical case definition, 53% (265/496). qPCR of negative culture samples after six months of observation was of diagnostic value retrospectively with but missed 58% of positives (109/353)., Conclusion: Leptospirosis disease burden estimates should consider the limitations of standard diagnostic tests. qPCR of multiple sample types should be used as a leading standard test for diagnosing acute leptospirosis., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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40. Pathogenic Leptospira Evolved a Unique Gene Family Comprised of Ricin B-Like Lectin Domain-Containing Cytotoxins.
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Chaurasia R, Marroquin AS, Vinetz JM, and Matthias MA
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Leptospirosis is a globally important neglected zoonotic disease. Previous data suggest that a family of virulence-modifying (VM) proteins (PF07598) is a distinctive feature of group I pathogenic Leptospira that evolved as important virulence determinants. Here, we show that one such VM protein, LA3490 (also known as Q8F0K3), is expressed by Leptospira interrogans serovar Lai, as a secreted genotoxin that is potently cytotoxic to human cells. Structural homology searches using Phyre2 suggested that VM proteins are novel R-type lectins containing tandem N-terminal ricin B-chain-like β-trefoil domains. Recombinant LA3490 (rLA3490) and an N-terminal fragment, t3490, containing only the predicted ricin B domain, bound to the terminal galactose and N-acetyl-galactosamine residues, asialofetuin, and directly competed for asialofetuin-binding sites with recombinant ricin B chain. t3490 alone was sufficient for binding, both to immobilized asialofetuin and to the HeLa cell surface but was neither internalized nor cytotoxic. Treatment of HeLa cells with rLA3490 led to cytoskeleton disassembly, caspase-3 activation, and nuclear fragmentation, and was rapidly cytolethal. rLA3490 had DNase activity on mammalian and bacterial plasmid DNA. The combination of cell surface binding, internalization, nuclear translocation, and DNase functions indicate that LA3490 and other VM proteins evolved as novel forms of the bacterial AB domain-containing toxin paradigm., Competing Interests: JV and spouse have an equity interest in LeptoX, which may have a future interest in licensing this work. The work reported here has been filed in patent applications from Yale University. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chaurasia, Marroquin, Vinetz and Matthias.)
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- 2022
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41. Nyssorhynchus darlingi genome-wide studies related to microgeographic dispersion and blood-seeking behavior.
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Alvarez MVN, Alonso DP, Kadri SM, Rufalco-Moutinho P, Bernardes IAF, de Mello ACF, Souto AC, Carrasco-Escobar G, Moreno M, Gamboa D, Vinetz JM, Conn JE, and Ribolla PEM
- Subjects
- Animals, Disease Vectors, Female, Genome-Wide Association Study, Mosquito Vectors genetics, Anopheles genetics, Malaria
- Abstract
Background: In Brazil, malaria is concentrated in the Amazon Basin, where more than 99% of the annual cases are reported. The main goal of this study was to investigate the population structure and genetic association of the biting behavior of Nyssorhynchus (also known as Anopheles) darlingi, the major malaria vector in the Amazon region of Brazil, using low-coverage genomic sequencing data., Methods: Samples were collected in the municipality of Mâncio Lima, Acre state, Brazil between 2016 and 2017. Different approaches using genotype imputation and no gene imputation for data treatment and low-coverage sequencing genotyping were performed. After the samples were genotyped, population stratification analysis was performed., Results: Weak but statistically significant stratification signatures were identified between subpopulations separated by distances of approximately 2-3 km. Genome-wide association studies (GWAS) were performed to compare indoor/outdoor biting behavior and blood-seeking at dusk/dawn. A statistically significant association was observed between biting behavior and single nucleotide polymorphism (SNP) markers adjacent to the gene associated with cytochrome P450 (CYP) 4H14, which is associated with insecticide resistance. A statistically significant association between blood-seeking periodicity and SNP markers adjacent to genes associated with the circadian cycle was also observed., Conclusion: The data presented here suggest that low-coverage whole-genome sequencing with adequate processing is a powerful tool to genetically characterize vector populations at a microgeographic scale in malaria transmission areas, as well as for use in GWAS. Female mosquitoes entering houses to take a blood meal may be related to a specific CYP4H14 allele, and female timing of blood-seeking is related to circadian rhythm genes., (© 2022. The Author(s).)
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- 2022
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42. A Phase 2 Randomized, Double-Blind, Placebo-controlled Trial of Oral Camostat Mesylate for Early Treatment of COVID-19 Outpatients Showed Shorter Illness Course and Attenuation of Loss of Smell and Taste.
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Chupp G, Spichler-Moffarah A, Søgaard OS, Esserman D, Dziura J, Danzig L, Chaurasia R, Patra KP, Salovey A, Nunez A, May J, Astorino L, Patel A, Halene S, Wang J, Hui P, Patel P, Lu J, Li F, Gan G, Parziale S, Katsovich L, Desir GV, and Vinetz JM
- Abstract
Importance: Early treatment of mild SARS-CoV-2 infection might lower the risk of clinical deterioration in COVID-19., Objective: To determine whether oral camostat mesylate would reduce upper respiratory SARS-CoV-2 viral load in newly diagnosed outpatients with mild COVID-19, and would lead to improvement in COVID-19 symptoms., Design: From June, 2020 to April, 2021, we conducted a randomized, double-blind, placebo-controlled phase 2 trial., Setting: Single site, academic medical center, outpatient setting in Connecticut, USA., Participants: Of 568 COVID-19 positive potential adult participants diagnosed within 3 days of study entry and assessed for eligibility, 70 were randomized and 498 were excluded (198 did not meet eligibility criteria, 37 were not interested, 265 were excluded for unknown or other reasons). The primary inclusion criteria were a positive SARS-CoV-2 nucleic acid amplification result in adults within 3 days of screening regardless of COVID-19 symptoms., Intervention: Treatment was 7 days of oral camostat mesylate, 200 mg po four times a day, or placebo., Main Outcomes and Measures: The primary outcome was reduction of 4-day log
10 nasopharyngeal swab viral load by 0.5 log10 compared to placebo. The main prespecified secondary outcome was reduction in symptom scores as measured by a quantitative Likert scale instrument, Flu-PRO-Plus modified to measure changes in smell/taste measured using FLU-PRO-Plus., Results: Participants receiving camostat had statistically significant lower quantitative symptom scores (FLU-Pro-Plus) at day 6, accelerated overall symptom resolution and notably improved taste/smell, and fatigue beginning at onset of intervention in the camostat mesylate group compared to placebo. Intention-to-treat analysis demonstrated that camostat mesylate was not associated with a reduction in 4-day log10 NP viral load compared to placebo., Conclusions and Relevance: The camostat group had more rapid resolution of COVID-19 symptoms and amelioration of the loss of taste and smell. Camostat compared to placebo was not associated with reduction in nasopharyngeal SARS-COV-2 viral load. Additional clinical trials are warranted to validate the role of camostat mesylate on SARS-CoV-2 infection in the treatment of mild COVID-19., Trial Registration: Clinicaltrials.gov, NCT04353284 (04/20/20)(https://clinicaltrials.gov/ct2/show/NCT04353284?term=camostat+%2C+yale&draw=2&rank=1).- Published
- 2022
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43. Evolutionary Insights into the Microneme-Secreted, Chitinase-Containing High-Molecular-Weight Protein Complexes Involved in Plasmodium Invasion of the Mosquito Midgut.
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Kaur H, Pacheco MA, Garber L, Escalante AA, and Vinetz JM
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- Animals, Biological Evolution, Chitinases genetics, Digestive System parasitology, Models, Biological, Models, Molecular, Molecular Weight, Multiprotein Complexes chemistry, Phylogeny, Plasmodium classification, Protein Conformation, Species Specificity, Structure-Activity Relationship, Chitinases metabolism, Culicidae parasitology, Host-Parasite Interactions, Microneme metabolism, Multiprotein Complexes metabolism, Plasmodium physiology
- Abstract
While general mechanisms by which Plasmodium ookinetes invade the mosquito midgut have been studied, details regarding the interface of the ookinete, specifically its barriers to invasion, such as the proteolytic milieu, the chitin-containing, protein cross-linked peritrophic matrix, and the midgut epithelium, remain to be understood. Here, we review our knowledge of Plasmodium chitinases and the mechanisms by which they mediate ookinetes crossing the peritrophic matrix. The integration of new genomic insights into previous findings advances our understanding of Plasmodium evolution. Recently obtained Plasmodium species genomic data enable identification of the conserved residues in the experimentally demonstrated hetero-multimeric, high-molecular-weight complex comprised of a short chitinase covalently linked to binding partners, von Willebrand factor A domain-related protein (WARP) and secreted ookinete adhesive protein (SOAP). Artificial intelligence-based high-resolution structural modeling using the DeepMind AlphaFold algorithm yielded highly informative three-dimensional structures and insights into how short chitinases, WARP, and SOAP may interact at the atomic level to form the ookinete-secreted peritrophic matrix invasion complex. Elucidating the significance of the divergence of ookinete-secreted micronemal proteins among Plasmodium species may lead to a better understanding of the ookinete invasion machinery and the coevolution of Plasmodium -mosquito interactions.
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- 2022
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44. SARS-CoV-2 expresses a microRNA-like small RNA able to selectively repress host genes.
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Pawlica P, Yario TA, White S, Wang J, Moss WN, Hui P, Vinetz JM, and Steitz JA
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- COVID-19 metabolism, COVID-19 virology, Host-Pathogen Interactions, Humans, RNA, Small Untranslated genetics, RNA, Viral genetics, SARS-CoV-2 genetics, Gene Expression Regulation, Viral, RNA, Small Untranslated metabolism, RNA, Viral metabolism, SARS-CoV-2 metabolism, Viral Proteins genetics
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease (COVID-19), continues to be a pressing health concern. In this study, we investigated the impact of SARS-CoV-2 infection on host microRNA (miRNA) populations in three human lung-derived cell lines, as well as in nasopharyngeal swabs from SARS-CoV-2-infected individuals. We did not detect any major and consistent differences in host miRNA levels after SARS-CoV-2 infection. However, we unexpectedly discovered a viral miRNA-like small RNA, named CoV2-miR-O7a (for SARS-CoV-2 miRNA-like ORF7a-derived small RNA). Its abundance ranges from low to moderate as compared to host miRNAs and it associates with Argonaute proteins-core components of the RNA interference pathway. We identify putative targets for CoV2-miR-O7a, including Basic Leucine Zipper ATF-Like Transcription Factor 2 (BATF2), which participates in interferon signaling. We demonstrate that CoV2-miR-O7a production relies on cellular machinery, yet is independent of Drosha protein, and is enhanced by the presence of a strong and evolutionarily conserved hairpin formed within the ORF7a sequence., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)
- Published
- 2021
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45. Clinical spectrum of endemic leptospirosis in relation to cytokine response.
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Dahanayaka NJ, Agampodi SB, Seneviratna I, Warnasekara J, Rajapakse R, Ranathunga K, Matthias M, and Vinetz JM
- Subjects
- Adult, Female, Follow-Up Studies, Hospitals, Teaching, Humans, Leptospirosis blood, Leptospirosis diagnosis, Longitudinal Studies, Male, Middle Aged, Prognosis, Prospective Studies, Sri Lanka epidemiology, Biomarkers blood, Cytokines blood, Endemic Diseases statistics & numerical data, Leptospira isolation & purification, Leptospirosis epidemiology
- Abstract
Objectives: To describe the clinical spectrum and the cytokine response of leptospirosis patients in an endemic setting of Sri Lanka., Methods: Patients presenting to the university teaching hospital, Anuradhapura, Sri Lanka with a leptospirosis-compatible illness were recruited over a period of 12 months starting from June 2012. Daily clinical and biochemical parameters of the patients were prospectively assessed with a follow-up of 14 days after discharge. A magnetic bead-based multiplex cytokine kit was used to detect 17 cytokines., Results: Of the 142 clinically suspected leptospirosis patients recruited, 47 were confirmed and, 29 cases were labeled as "probable." Thrombocytopenia and leukocytosis were observed at least once during the hospital stay among 76(54%) and 39(28%) patients, respectively. Acute kidney injury was observed in 31 patients (22%) and it was significantly higher among confirmed and probable cases. Hu TNF-α and IL-1β were detected only in patients without complications. Hu MIP-1b levels were significantly higher among patients with complications. During the convalescence period, all tested serum cytokine levels were lower compared to the acute sample, except for IL-8. The cytokine response during the acute phase clustered in four different groups. High serum creatinine was associated GM-CSF, high IL-5 and IL-6 level were correlates with lung involvement and saturation drop. The patients with high billirubin (direct)>7 mmol/l had high IL-13 levels., Conclusions: Results of this study confirms that the knowledge on cytokine response in leptospirosis could be more complex than other similar tropical disease, and biosignatures that provide diagnostic and prognostic information for human leptospirosis remain to be discovered., Competing Interests: No authors have competing interests.
- Published
- 2021
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46. Asymptomatic Plasmodium vivax malaria in the Brazilian Amazon: Submicroscopic parasitemic blood infects Nyssorhynchus darlingi.
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Almeida GG, Costa PAC, Araujo MDS, Gomes GR, Carvalho AF, Figueiredo MM, Pereira DB, Tada MS, Medeiros JF, Soares IDS, Carvalho LH, Kano FS, Castro MC, Vinetz JM, Golenbock DT, Antonelli LRDV, and Gazzinelli RT
- Subjects
- Animals, Anopheles physiology, Asymptomatic Infections epidemiology, Blood parasitology, Brazil epidemiology, Cohort Studies, Cross-Sectional Studies, Female, Humans, Malaria, Vivax epidemiology, Malaria, Vivax parasitology, Male, Middle Aged, Plasmodium vivax genetics, Seasons, Anopheles parasitology, Malaria, Vivax transmission, Plasmodium vivax physiology
- Abstract
Individuals with asymptomatic infection due to Plasmodium vivax are posited to be important reservoirs of malaria transmission in endemic regions. Here we studied a cohort of P. vivax malaria patients in a suburban area in the Brazilian Amazon. Overall 1,120 individuals were screened for P. vivax infection and 108 (9.6%) had parasitemia detected by qPCR but not by microscopy. Asymptomatic individuals had higher levels of antibodies against P. vivax and similar hematological and biochemical parameters compared to uninfected controls. Blood from asymptomatic individuals with very low parasitemia transmitted P. vivax to the main local vector, Nyssorhynchus darlingi. Lower mosquito infectivity rates were observed when blood from asymptomatic individuals was used in the membrane feeding assay. While blood from symptomatic patients infected 43.4% (199/458) of the mosquitoes, blood from asymptomatic infected 2.5% (43/1,719). However, several asymptomatic individuals maintained parasitemia for several weeks indicating their potential role as an infectious reservoir. These results suggest that asymptomatic individuals are an important source of malaria parasites and Science and Technology for Vaccines granted by Conselho Nacional de may contribute to the transmission of P. vivax in low-endemicity areas of malaria., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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47. Optimizing the microscopic agglutination test (MAT) panel for the diagnosis of Leptospirosis in a low resource, hyper-endemic setting with varied microgeographic variation in reactivity.
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Jayasundara D, Gamage C, Senavirathna I, Warnasekara J, Matthias MA, Vinetz JM, and Agampodi S
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- Adult, Aged, Antibodies, Bacterial blood, Endemic Diseases, Enzyme-Linked Immunosorbent Assay methods, Female, Humans, Leptospira, Leptospirosis epidemiology, Male, Middle Aged, Polymerase Chain Reaction, Retrospective Studies, Sensitivity and Specificity, Sri Lanka epidemiology, Young Adult, Agglutination Tests methods, Leptospirosis blood, Leptospirosis diagnosis, Serologic Tests
- Abstract
The microscopic agglutination test (MAT) is the standard serological reference test for the diagnosis of leptospirosis, despite being a technically demanding and laborious procedure. The use of a locally optimised MAT panel is considered essential for proper performance and interpretation of results. This paper describes the procedure of selecting such an optimised panel for Sri Lanka, a country hyper-endemic for leptospirosis. MAT was performed using 24 strains on 1132 serum samples collected from patients presenting with acute undifferentiated fever. Of 24 strains, 15 were selected as the optimised panel, while only 11% of serum samples showed positivity. A geographical variation in predominantly reactive serovars was observed, whereas reactivity was low with the saprophytic strain Patoc. Testing with paired sera yielded a higher sensitivity but provided only a retrospective diagnosis. Serological tests based on ELISA with complementary molecular diagnosis using PCR are a feasible and robust alternative approach to diagnose leptospirosis in countries having a higher burden of the disease., Competing Interests: The authors have declared that no competing interests exist.
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- 2021
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48. Correction: 12 Novel clonal groups of Leptospira infecting humans in multiple contrasting epidemiological contexts in Sri Lanka.
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Jayasundara D, Senavirathna I, Warnasekara J, Gamage C, Siribaddana S, Kularatne SAM, Matthias M, Mariet JF, Picardeau M, Agampodi S, and Vinetz JM
- Abstract
[This corrects the article DOI: 10.1371/journal.pntd.0009272.].
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- 2021
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49. New Records of Anopheles benarrochi B (Diptera: Culicidae) in Malaria Hotspots in the Amazon Regions of Ecuador and Peru.
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Morales Viteri D, Herrera-Varela M, Albuja M, Quiroga C, Diaz G, Del Aguila Morante C, Ramirez D, Vinetz JM, Bickersmith SA, and Conn JE
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- Animals, Ecuador, Malaria, Peru, Animal Distribution, Anopheles physiology, Mosquito Vectors physiology
- Abstract
The increase in malaria transmission in the Amazon region motivated vector control units of the Ministry of Health of Ecuador and Peru to investigate Anopheles (Diptera: Culicidae) species present in transmission hotspots. Mosquitoes were collected using prokopack aspirators and CDC light traps (Ecuador) and human landing catch in Peru. In Ecuador, 84 Anopheles were captured from Pastaza, Morona Santiago, and Orellana provinces and identified morphologically [An. (An.) apicimacula Dyar and Knab, An. (Nys.) near benarrochi, An. (Nys.) near oswaldoi, An. (Nys.) near strodei, An. (An.) nimbus (Theobald, 1902), and An. (Nyssorhynchus) sp.]. In Peru, 1,150 Anopheles were collected in Andoas District. A subsample of 166 specimens was stored under silica and identified as An. near oswaldoi, An. darlingi, and An. (An.) mattogrossensis Lutz and Neiva. COI barcode region sequences were obtained for 137 adults (107 from Peru, 30 from Ecuador) identified by ITS2 PCR-RFLP as An. benarrochi Gabaldon, Cova Garcia, and Lopez and retained in the final analysis. Haplotypes from the present study plus An. benarrochi B GenBank sequences grouped separately from Brazilian An. benarrochi GenBank sequences by 44 mutation steps, indicating that the present study specimens were An. benarrochi B. Our findings confirm the presence of An. benarrochi B in Ecuador and reported here for the first time from the Amazonian provinces of Orellana and Morona Santiago. Furthermore, we confirm that the species collected in Andoas District in the Datem del Maranon Province, Peru, is An. benarrochi B, and we observed that it is highly anthropophilic. Overall, the known distribution of An. benarrochi B has been extended and includes southern Colombia, much of Peru and eastern Ecuador., (© The Author(s) 2021. Published by Oxford University Press on behalf of Entomological Society of America.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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50. Temporal and Microspatial Heterogeneity in Transmission Dynamics of Coendemic Plasmodium vivax and Plasmodium falciparum in Two Rural Cohort Populations in the Peruvian Amazon.
- Author
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Rosas-Aguirre A, Guzman-Guzman M, Chuquiyauri R, Moreno M, Manrique P, Ramirez R, Carrasco-Escobar G, Rodriguez H, Speybroeck N, Conn JE, Gamboa D, Vinetz JM, and Llanos-Cuentas A
- Subjects
- Cohort Studies, Humans, Peru epidemiology, Plasmodium falciparum, Plasmodium vivax, Prevalence, Malaria, Falciparum epidemiology, Malaria, Falciparum transmission, Malaria, Vivax epidemiology, Malaria, Vivax transmission
- Abstract
Background: Malaria is highly heterogeneous: its changing malaria microepidemiology needs to be addressed to support malaria elimination efforts at the regional level., Methods: A 3-year, population-based cohort study in 2 settings in the Peruvian Amazon (Lupuna, Cahuide) followed participants by passive and active case detection from January 2013 to December 2015. Incidence and prevalence rates were estimated using microscopy and polymerase chain reaction (PCR)., Results: Lupuna registered 1828 infections (1708 Plasmodium vivax, 120 Plasmodium falciparum; incidence was 80.7 infections/100 person-years (95% confidence interval [CI] , 77.1-84.5). Cahuide detected 1046 infections (1024 P vivax, 20 P falciparum, 2 mixed); incidence was 40.2 infections/100 person-years (95% CI, 37.9-42.7). Recurrent P vivax infections predominated onwards from 2013. According to PCR data, submicroscopic predominated over microscopic infections, especially in periods of low transmission. The integration of parasitological, entomological, and environmental observations evidenced an intense and seasonal transmission resilient to standard control measures in Lupuna and a persistent residual transmission after severe outbreaks were intensively handled in Cahuide., Conclusions: In 2 exemplars of complex local malaria transmission, standard control strategies failed to eliminate submicroscopic and hypnozoite reservoirs, enabling persistent transmission., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2021
- Full Text
- View/download PDF
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