Search

Since the onset of the COVID-19 outbreak, numerous articles have highlighted a possible link between COVID-19 vaccination or infection and Herpesviridae co-infection or reactivation. The authors conducted an exhaustive literature review on this topic, the results of which are presented individually for each member of the Herpesviridae family: Herpes Simplex Virus (HSV) types-1 (HSV-1) and 2 (HSV-2); Varicella-Zoster Virus (VZV); Epstein-Barr Virus (EBV); Cytomegalovirus (CMV); HHV-6; HHV-7; and HHV-8. These human herpesviruses can serve as prognostic markers for the COVID-19 infection and may even underlie some of the clinical manifestations initially attributed to SARS-CoV-2. In addition to SARS-CoV-2 infection, all corresponding vaccines approved to date in Europe appear capable of inducing herpesvirus reactivation. It is important to consider all viruses of the Herpesviridae family when managing patients infected with or recently vaccinated against COVID-19.

Woody canker diseases caused by fungi of the Botryosphaeriaceae family are producing increasing losses in many economically important woody crops, including almond. To develop a molecular tool for the detection and quantification of the most aggressive and threatening species is of main importance. This will help to prevent the introduction of these pathogens in new orchards and to conveniently apply the appropriate control measures. Three reliable, sensitive and specific duplex qPCR assays using TaqMan probes have been designed for the detection and quantification of (a) Neofusicoccum parvum and the Neofusicoccum genus, (b) N. parvum and the Botryosphaeriaceae family and (c) Botryosphaeria dothidea and the Botryosphaeriaceae family. The multiplex qPCR protocols have been validated on artificially and naturally infected plants. Direct systems to process plant materials, without DNA purification, allowed high-throughput detection of Botryosphaeriaceae targets even in asymptomatic tissues. These results validate the qPCR using the direct sample preparation method as a valuable tool for Botryosphaeria dieback diagnosis allowing a large-scale analysis and the preventive detection of latent infection.

Alphaherpesviruses infect humans and most animals. They can cause severe morbidity and mortality. The pseudorabies virus (PRV) is a neurotropic alphaherpesvirus that can infect most mammals. The PRV persists in the host by establishing a latent infection, and stressful stimuli can induce the latent viruses to reactivate and cause recurrent diseases. The current strategies of antiviral drug therapy and vaccine immunization are ineffective in eliminating these viruses from the infected host. Moreover, overspecialized and complex models are also a major obstacle to the elucidation of the mechanisms involved in the latency and reactivation of the PRV. Here, we present a streamlined model of the latent infection and reactivation of the PRV. A latent infection established in N2a cells infected with the PRV at a low multiplicity of infection (MOI) and maintained at 42 °C. The latent PRV was reactivated when the infected cells were transferred to 37 °C for 12 to 72 h. When the above process was repeated with a UL54-deleted PRV mutant, it was observed that the UL54 deletion did not affect viral latency. However, viral reactivation was limited and delayed. This study establishes a powerful and streamlined model to simulate PRV latency and reveals the potential role of temperature in PRV reactivation and disease. Meanwhile, the key role of the early gene UL54 in the latency and reactivation of PRV was initially elucidated.

Recent global evidences showed that asymptomatic blood donor carriers of Leishmania infection will appear as a threat for blood transfusions recipients in endemic areas. As yet, there is no appropriate diagnostic procedure for detecting infection of blood donors in blood banks.The present study was aimed to apply various current diagnostic tests among blood donors in an endemic area of visceral leishmaniasis (VL), Ardabil Province, northwestern Iran. Blood samples were gathered from 860 blood donors in endemic areas of the province between 2017 and 2018, at eight blood donation centers. These samples was assessed using microculture, serological (DAT and rK39-ICT) and molecular based (conventional kDNA-PCR and HRM-PCR) tests.Of 860 eligible donors, 24 (2.8%) were seropositive for VL by DAT, and 388 (45%) were positive by kDNA-PCR. Moreover, 19 (19/860) were positive for both of them. Out of 19 subjects, 5.3% (1/19) was positive by rK39-ICT, 10.5% (2/19), and 79% (15/19) were detected positive in microculture and HRM-PCR methods, respectively. Nineteen donors were followed up for 2 years, of which 16 (84.2%) had a serological conversion, and 4 (21%) were positive by kDNA-PCR. The sensitivity of kDNA-PCR, and HRM-PCR procedures in detecting Leishmania parasite was found to be 98.7%, and 79%, respectively.Our findings justify the use of kDNA-PCR as a convenient and sensitive tool for screening subjects with leishmanial latent infection in blood banks at least in endemic regions. In these areas, however, a PCR-based test should be used to validate Leishmania infection among seropositive donors.

Some risk factors for severe coronavirus disease 2019 (COVID-19) have been identified, including age, race, and obesity. However, 20%–50% of severe cases occur in the absence of these factors. Cytomegalovirus (CMV) is a herpesvirus that infects about 50% of all individuals worldwide and is among the most significant nongenetic determinants of immune system. We hypothesized that latent CMV infection might influence the severity of COVID-19. Our analyses demonstrate that CMV seropositivity is associated with more than twice the risk of hospitalization due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immune profiling of blood and CMV DNA quantitative polymerase chain reaction in a subset of patients for whom respiratory tract samples were available revealed altered T-cell activation profiles in absence of extensive CMV replication in the upper respiratory tract. These data suggest a potential role for CMV-driven immune perturbations in affecting the outcome of SARS-CoV-2 infection and may have implications for the discrepancies in COVID-19 severity between different human populations.

ilustraciones, diagramas En humanos la infección por P. aeruginosa es controlada por múltiples factores de virulencia y es una de las causas más recurrentes y graves de infecciones asociadas a la atención en salud. Por lo tanto, el objetivo general de este estudio fue caracterizar los perfiles genómicos de virulencia en aislados clínicos de Pseudomonas aeruginosa provenientes de un hospital universitario de Bogotá- Colombia, utilizando la tecnología de secuenciación de genoma completo (WGS). Este estudio prospectivo se realizó durante los años 2019 y 2021, en donde se secuenciaron 54 aislamientos provenientes de 37 pacientes de los servicios de UCI, hospitalización y Unidad quirúrgica, utilizando las plataformas illumina y Oxford Nanopore. En los genomas se encontraron un total de 246 genes de virulencia, encontrando la presencia de genes de gran importancia en la virulencia de esta bacteria, como el gen pilA que se detectó en el 48,1% de los aislamientos y el gen algD en el 100%. Para las toxinas la prevalencia fue para exoU de (16,6%), exoT (92,5%), exoS (79,6%) y exoY (88,8%). Adicionalmente se encontró la presencia de 16 secuencio-tipos (ST) ya reportados y se encontraron 13 ST nuevos. En conclusión, el uso de tecnologías como WGS permitió determinar el perfil de virulencia de aislados clínicos de P. aeruginosa, logrando un acercamiento global a los perfiles de virulencia de los aislamientos clínicos de esta bacteria en el país, siendo el primer reporte de la prevalencia de más de 200 genes de virulencia en Colombia para P. aeruginosa. (Texto tomado de la fuente) In humans, P. aeruginosa infection is controlled by multiple virulence factors and is one of the most recurrent and serious causes of healthcare-associated infections. The aim of this study was to characterize the virulence genomic profiles in clinical isolates of Pseudomonas aeruginosa from a hospital in Bogotá-Colombia, using whole genome sequencing (WGS) technology. A prospective study was carried out during the years 2019 and 2021, where 54 isolates from 37 patients from both the ICU and hospitalization services, and operating rooms were sequenced, using the illumina and Oxford Nanopore platforms. A total of 246 virulence genes were found in the genomes, finding the presence of genes of great importance in the virulence of this bacterium, such as the pilA gene that was detected in 48.1% of the isolates and the algD gene that found in the 100% of them. For toxins, the prevalence was for exoU de (16.6%), exoT (92.5%), exoS (79.6%) and exoY (88.8%). Additionally, the presence of 16 sequence-types (ST) already reported and 13 new ST were found. In conclusion, the use of technologies such as WGS made it possible to determine the virulence profile of clinical isolates of P. aeruginosa, achieving a global approach to the virulence profiles of the clinical isolates of this bacterium in the country, being the first report of the prevalence of more than 200 virulence genes in Colombia for P. aeruginosa. Maestría Magíster en Ciencias - Microbiología Biología molecular de agentes infecciosos

Peer reviewed: True, Human cytomegalovirus (HCMV) infection and periodic reactivation is, generally, well controlled by adaptative immune responses in the healthy. In older people, overt HCMV disease is rarely seen despite the association of HCMV with increased risk of mortality; evidence from studies of unwell aged populations suggest that HCMV seropositivity is an important co-morbidity factor. HCMV genomes have been detected in urine from older donors, suggesting that the immune response prevents systemic disease but possibly immunomodulation due to lifelong viral carriage may alter its efficacy at peripheral tissue sites. Previously we have demonstrated that there were no age-related expansions of T cell responses to HCMV or increase in latent viral carriage with age and these T cells produced anti-viral cytokines and viremia was very rarely detected. To investigate the efficacy of anti-HCMV responses with increasing age, we used an in vitro Viral Dissemination Assay (VDA) using autologous dermal fibroblasts to determine the anti-viral effector capacity of total PBMC, as well as important subsets (T cells, NK cells). In parallel we assessed components of the humoral response (antibody neutralization) and combined this with qPCR detection of HCMV in blood, saliva and urine in a cohort of young and old donors. Consistent with previous studies, we again show HCMV specific cIL-10, IFNγ and TNFα T cell responses to peptides did not show an age-related defect. However, assessment of direct anti-viral cellular and antibody-mediated adaptive immune responses using the VDA shows that older donors are significantly less able to control viral dissemination in an in vitro assay compared to young donors. Corroborating this observation, we detected viral genomes in saliva samples only from older donors, these donors had a defect in cellular control of viral spread in our in vitro assay. Phenotyping of fibroblasts used in this study shows expression of a number of checkpoint inhibitor ligands which may contribute to the defects observed. The potential to therapeutically intervene in checkpoint inhibitor pathways to prevent HCMV reactivation in the unwell aged is an exciting avenue to explore., S Jackson gratefully acknowledges pump-prime funding from the NIHR Cambridge Bioresource Immunity, Infection and Inflammation theme.

Im Rahmen der ambitionierten „End TB strategy“ der Weltgesundheitsorganisation (WHO) wurde für Niedriginzidenzländer das Ziel definiert, eine Elimination der TB als Gesundheitsproblem bis zum Jahr 2050 zu erreichen. Ein wichtiger Bestandteil einer erfolgreichen TB-Kontrolle ist dabei nicht nur die Identifikation von Risikogruppen, sondern auch die Diagnose und Behandlung der LTBI sowie die optimierte Therapie der manifesten TB. Kinder stellen eine besonders vulnerable Gruppe für TB dar, da sie im Vergleich zu Erwachsenen ein erhöhtes Risiko für schwere, disseminierte Verläufe wie eine TBM haben. Wir konnten zeigen, dass ein Screening auf TB mit einem IGRA-Test bei unbegleiteten minderjährigen Flüchtlingen auch bei großen Flüchtlingszahlen durchführbar ist und dass nicht nur Kinder- und Jugendliche aus Hochinzidenzländern, sondern auch aus Ländern mit niedriger TB-Inzidenz aufgrund der Bedingungen während der Flucht und bei Unterbringung in Massenunterkünften ein hohes Risiko für eine TB-Infektion aufweisen. Die Flüchtlinge, bei denen eine LTBI diagnostiziert wurde, erhielten eine dreimonatige Chemoprävention mit RMP und INH. Die Therapie wurde insgesamt gut vertragen, die häufigste Nebenwirkung waren transiente gastrointestinale Beschwerden. Dabei stellte sich die Versorgung einer Patientengruppe, die häufig nur temporär untergebracht ist, als herausfordernd dar. Da eine LTBI keine meldepflichtige Erkrankung ist, ist die Nachverfolgung der betroffenen Kinder und Jugendlichen zusätzlich erschwert und damit das Risiko einer nicht adäquat durchgeführten Therapie erhöht. In einer weiteren Erhebungsstudie konnten wir zeigen, dass pädiatrische Pneumologen und Infektiologen in Deutschland, Österreich und der Schweiz meist nur wenige Kinder pro Jahr auf eine TB hin untersuchen und damit das Risiko besteht, dass das Wissen und Erfahrungen zur Diagnostik und Therapie dieser Erkrankung außerhalb von Zentren deutlich abnehmen. Dies zeigte sich zum einem in einer deutlichen Heterogenität im Management der LTBI, zum anderen in der häufigen Verwendung von langwierigen INH-Monotherapien. Kürzere Kombinationstherapien von INH und RMP sind äußerst effektiv in der Prävention einer TB und mit einer deutlich besseren Medikamentenadhärenz assoziiert als INH-Monotherapien. Eine Therapie ohne Vorliegen von Symptomen durchzuführen, stellt eine große Herausforderung für die Patient*innen dar und es bedarf dringend der Evaluation noch kürzerer Therapien der LTBI auch bei Kindern. Da sich die Prinzipien der Therapie der TB für Erwachsene und Kinder nicht unterscheiden, sollten bei Kindern dieselben Serumspiegel der TB-Medikamente angestrebt werden, wie die, deren Effektivität in Studien bei Erwachsenen gut belegt sind. Wir konnten in einer ersten pharmakokinetischen Studie an 27 Kindern mit pulmonaler TB im Alter von 2-14 Jahren zeigen, dass Kinder niedrigere maximale Serumspiegel und eine verminderte AUC nach einer RMP-Dosis von 10mg/kg KG aufweisen als Erwachsene nach einer RMP-Standarddosis. Für eine adäquate Therapie benötigen Kinder deutlich höhere mg/kg Dosierungen als Erwachsene, was insbesondere für schwere Erkrankungsformen der TB äußerst relevant ist. Eine der schwersten Erkrankungsformen der TB stellt die TBM dar, für die vor allem jüngere Kinder ein hohes Risiko haben. Eine frühzeitige Diagnosestellung und Einleitung der Therapie sind maßgeblich für das spätere Outcome. In einer ersten Arbeit im Rahmen des europäischen Netzwerkes „ptbnet“ haben wir die Anwendung immunologischer und mikrobiologischer Diagnostikverfahren bei Kindern mit TBM in Niedriginzidenzländern untersucht. Siebenundzwanzig europäische Zentren nahmen an dieser multizentrischen, retrospektiven Studie teil. Wir konnten zeigen, dass die aktuellen diagnostischen Tests in Kombination zwar bei mehr als 80% der Kinder mit TBM-Verdacht einen zusätzlichen Hinweis auf eine TB geben, bei fast 20% muss eine Therapie jedoch allein aufgrund des Verdachtes eingeleitet werden. Es bedarf daher dringend einfach anzuwendender, optimalerweise direkt verfügbarer Diagnostika, um alle Kinder mit TBM zu erfassen. In der Auswertung des Managements und Outcomes der TBM in derselben Kohorte zeigte sich eine hohe Morbidität und Mortalität, obwohl sich nur wenige Kinder in einem fortgeschrittenen Erkrankungsstadium präsentierten. Wir konnten den mikrobiologischen Nachweis von M. tuberculosis sowie die Notwendigkeit einer neurochirurgischen Intervention und einer mechanischen Beatmung als Risikofaktoren für einen ungünstigen Verlauf identifizieren. Bei einem relevanten Anteil der Kinder wurden die aktuellen Dosisempfehlungen für die antituberkulösen Medikamente sowie die anti-inflammatorische Therapie nicht umgesetzt und niedrigere Dosen verwendet. Zusammenfassend konnten wir in unseren Arbeiten zeigen, dass bei Kindern und Jugendlichen das Screening auf TB in Risikogruppen durchführbar und notwendig ist, dass die diagnostischen Möglichkeiten einer TB insbesondere für die schwere Erkrankungsform einer TBM eine unzureichende Sensitivität aufweisen und dass für das Management und Therapie der TB bei Kindern weiterhin ein Optimierungsbedarf besteht. Die konsequente Detektion von LTBI/TB im Rahmen von Umgebungsuntersuchungen und Screening von Risikogruppen sowie die Therapie der LTBI mit kürzeren, vereinfachten Therapien stellen die wichtigsten Maßnahmen in Niedriginzidenzländern dar, um das Ziel einer TB-Elimination zu erreichen. Zur Senkung der Morbidität und Mortalität schwerer Erkrankungsformen sind die Generierung und Anwendung weiterer Evidenz aus Therapiestudien zur Optimierung der Versorgung essentiell. In Niedriginzidenzländern ist das Risiko für eine abnehmende Expertise hoch und es bedarf Maßnahmen wie kontinuierlicher Fortbildungsangebote und aktueller Leitlinien, um das Bewusstsein für das Vorhandensein von TB bei Kindern zu verbessern. Die Zusammenarbeit und der Austausch in Netzwerken wie beispielsweise dem ptbnet tragen hierzu maßgeblich bei.

Ying Zhang,1– 3,* Li-Si Zeng,4,* Juan Wang,5,* Wen-Qi Cai,2,3 Weiwen Cui,6 Tong-Jun Song,7 Xiao-Chun Peng,2,8 Zhaowu Ma,2,3 Ying Xiang,2,3 Shu-Zhong Cui,4 Hong-Wu Xin2,3 1Department of Gastroenterology, Chun’an County First People’s Hospital (Zhejiang Provincial People’s Hospital Chun’an Branch), Hangzhou, Zhejiang Province, 311700, People’s Republic of China; 2Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, 434023, People’s Republic of China; 3Department of Molecular Biology and Biochemistry, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, 434023, People’s Republic of China; 4State Key Laboratory of Respiratory Disease, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510095, People’s Republic of China; 5Department of Obstetrics and Gynecology, Lianjiang People’s Hospital, Guangdong, 524400, People’s Republic of China; 6Department of Bioengineering, University of California, Berkeley, CA, 94720, USA; 7Department of Neurosurgery, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong Province, 518104, People’s Republic of China; 8Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, 434023, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong-Wu Xin; Ying XiangLaboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, 1 Nanhuan Road, Jingzhou, Hubei, 434023, People’s Republic of ChinaTel +86 13311055391; +86 15107212530Fax +0716-8062633Email hongwu_xin@126.com; xying316@163.comAbstract: Herpes simplex viruses (HSVs) often cause latent infection for a lifetime, leading to repeated recurrence. HSVs have been engineered as oncolytic HSVs. The mechanism of the latent infection and recurrence remains largely unknown, which brings great challenges and limitations to eliminate HSVs in clinic and engineer safe oHSVs. Here, we systematically reviewed the latest development of the multi-step complex process of HSV latency and reactivation. Significantly, we first summarized the three HSV latent infection pathways, analyzed the structure and expression of the LAT1 and LAT2 of HSV-1 and HSV-2, proposed the regulation of LAT expression by four pathways, and dissected the function of LAT mediated by five LAT products of miRNAs, sRNAs, lncRNAs, sncRNAs and ORFs. We further analyzed that application of HSV LAT deletion mutants in HSV vaccines and oHSVs. Our review showed that deleting LAT significantly reduced the latency and reactivation of HSV, providing new ideas for the future development of safe and effective HSV therapeutics, vaccines and oHSVs. In addition, we proposed that RNA silencing or RNA interference may play an important role in HSV latency and reactivation, which is worth validating in future.Keywords: non-coding RNA, small RNA, oncolytic virus, herpes simplex virus, HSV, latent infection, latency-associated transcripts, LATs

Herpes simplex viruses (HSVs) often cause latent infection for a lifetime, leading to repeated recurrence. HSVs have been engineered as oncolytic HSVs. The mechanism of the latent infection and recurrence remains largely unknown, which brings great challenges and limitations to eliminate HSVs in clinic and engineer safe oHSVs. Here, we systematically reviewed the latest development of the multi-step complex process of HSV latency and reactivation. Significantly, we first summarized the three HSV latent infection pathways, analyzed the structure and expression of the LAT1 and LAT2 of HSV-1 and HSV-2, proposed the regulation of LAT expression by four pathways, and dissected the function of LAT mediated by five LAT products of miRNAs, sRNAs, lncRNAs, sncRNAs and ORFs. We further analyzed that application of HSV LAT deletion mutants in HSV vaccines and oHSVs. Our review showed that deleting LAT significantly reduced the latency and reactivation of HSV, providing new ideas for the future development of safe and effective HSV therapeutics, vaccines and oHSVs. In addition, we proposed that RNA silencing or RNA interference may play an important role in HSV latency and reactivation, which is worth validating in future.

Background: To screen specific metabolic markers serum metabolic biomarkers which can achieve the main monitoring indicators to evaluate the development from latent infection to active tuberculosis infection, and analysis its underlying mechanisms and functions. Methods: Four groups of serum, including healthy control, latent infection, drug sensitivity (DS), and drug resistant tuberculosis, were collected. The metabolites in all serum samples were extracted by oscillatory, deproteinization, and then were detected by LC-MS/MS analysis. Normalization by Pareto-scaling method, the difference analysis was carried out by Metaboanalyst 4.0 software, one-way ANOVA analysis among groups showed that p-value ≤0.05 was regarded as a different metabolite. To clarify the dynamic changes and functions of differential metabolites with disease progression, and explore its significance and mechanism as a marker by further cluster analysis, functional enrichment analysis, and relative content change analysis of differential metabolites. Results: There were 565 significantly different metabolites in four groups. Differential metabolites, including Indole-3-acetaldehyde, Theophylline, Inosine and Prostaglandin H2, etc., may be the key serum biomarkers to diagnose the period of latent infection of Mycobacterium tuberculosis (M. tuberculosis). which was closely related to Amino acid metabolism, Biosynthesis of other secondary metabolites, Nucleotide metabolism, Endocrine system, Immune system, Lipid metabolism, and Nervous system. Conclusion: Indole-3-acetaldehyde, Theophylline, Inosine, and Prostaglandin H2, the 4 metabolites may be potential markers diagnosing the period of latent infection of M. tuberculosis. Meanwhile, Inosine and Prostaglandin E1 can become potential biomarkers for the diagnosis of latent infection, and Theophylline and Cotinine 1 can be used as potential markers to monitor disease progression, which established strategy provided promising clinical application prospects for the development of disease assessment by combining small molecule metabolic markers to improve the sensitivity and specificity of disease diagnosis.

PurposeInformation is limited about adherence to practice guidelines in patients with hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV infection receiving anticancer treatment.MethodsNewly diagnosed adult cancer patients were enrolled in a multicenter, prospective cohort study (SWOG S1204) during 2013-2017 to evaluate the prevalence of HBV, HCV, or HIV in patients initiating anticancer treatment. At 6months, records of virus-positive patients were reviewed for antiviral therapy use; anticancer treatment dose reduction; and HBV reactivation (elevated viral load). Categorical variables were compared using chi-square or Fisher's exact test.ResultsOf 3055 enrolled patients with viral testing, 230 had chronic or past HBV, HCV, or HIV with 6-month follow-up data (chronic HBV, 15 patients; past HBV, 158; HCV, 49; HIV, 30). Twenty percent (3/15) of chronic HBV and 11% (17/158) of past HBV patients were co-infected with HCV and/or HIV. Rates of antiviral therapy use by 6months were as follows: chronic HBV, 85% (11/13); past HBV receiving anti-B cell therapy, 60% (3/5); past HBV receiving systemic anticancer therapy without anti-B cell therapy, 8% (8/105); HCV, 6% (2/35); and HIV, 90% (19/21). Among patients with available data, anticancer treatment dose was reduced in 1 of 145 patients with past HBV and 1 of 42 with HCV. HBV reactivation occurred in 1 of 15 patients with chronic HBV; this patient was not receiving antiviral therapy.ConclusionMany patients with cancer and viral infections either do not receive guideline-recommended antiviral treatment or receive antiviral treatment that is not recommended in guidelines. Further education is needed to improve adherence to guidelines.

Background Infections with human papillomaviruses (HPVs) may enter a latent state, and eventually become reactivated following loss of immune control. It is unclear what proportion of incident HPV detections are reactivations of previous latent infections vs new transmissions. Methods The HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) cohort study prospectively followed young newly formed heterosexual partners recruited between 2005 and 2011 in Montréal, Canada. We calculated the fraction of incident HPV detections nonattributable to sexual transmission risk factors with a Bayesian Markov model. Results are the median (2.5th-97.5th percentiles) of the estimated posterior distribution. Results A total of 544 type-specific incident HPV detection events occurred in 849 participants; 33% of incident HPV detections occurred in participants whose HITCH partners were negative for that HPV type and who reported no other sex partners over follow-up. We estimate that 43% (38%–48%) of all incident HPV detections in this population were not attributable to recent sexual transmission and might be potentially reactivation of latent infections. Conclusions A positive HPV test result in many cases may be a reactivated past infection, rather than a new infection from recent sexual behaviors or partner infidelity. The potential for reactivation of latent infections in previously HPV-negative women should be considered in the context of cervical cancer screening.

The surface polysacharide arabinomannan (AM) and related glycolipid lipoarabinomannan (LAM) play critical roles in tuberculosis pathogenesis. Human antibody responses to AM/LAM are heterogenous and knowledge of reactivity to specific glycan epitopes at the monoclonal level is limited, especially in individuals who can control M. tuberculosis infection. We generated human IgG mAbs to AM/LAM from B cells of two asymptomatic individuals exposed to or latently infected with M. tuberculosis. Here, we show that two of these mAbs have high affinity to AM/LAM, are non-competing, and recognize different glycan epitopes distinct from other anti-AM/LAM mAbs reported. Both mAbs recognize virulent M. tuberculosis and nontuberculous mycobacteria with marked differences, can be used for the detection of urinary LAM, and can detect M. tuberculosis and LAM in infected lungs. These mAbs enhance our understanding of the spectrum of antibodies to AM/LAM epitopes in humans and are valuable for tuberculosis diagnostic and research applications., Elise Ishida et al. generate human monoclonal antibodies that can selectively recognize specific oligosaccharide epitopes of the polysaccharides arabinomannan and lipoarabinomannan, which are critical for M. tuberculosis pathogenesis. The authors demonstrate the utility of these antibodies in both diagnostic and laboratory settings, making them important tools for M. tuberculosis research.

Most of the HIV DNA in infected individuals is noninfectious because of deleterious mutations. However, it is unclear how much of the transcribed HIV RNA is potentially infectious or defective. To address this question, we developed and validated a novel intact viral RNA assay (IVRA) that uses droplet digital reverse transcriptase PCR (dd-RT-PCR) for the commonly mutated packaging signal (Psi) and Rev response element (RRE) regions (from the intact proviral DNA assay [IPDA]) to quantify likely intact (Psi(+) RRE(+)), 3′ defective (Psi(+) RRE(−)), and 5′ defective (Psi(−) RRE(+)) HIV RNA. We then applied the IPDA and IVRA to quantify intact and defective HIV DNA and RNA from peripheral CD4(+) T cells from 9 antiretroviral therapy (ART)-suppressed individuals. Levels of 3′ defective HIV DNA were not significantly different from those of 5′ defective HIV DNA, and both were higher than intact HIV DNA. In contrast, 3′ defective HIV RNA (median 86 copies/10(6) cells; 94% of HIV RNA) was much more abundant than 5′ defective (2.1 copies/10(6) cells; 5.6%) or intact (0.6 copies/10(6) cells

Mango (

Currently, there are no particularly effective biomarkers to distinguish between latent tuberculosis infection (LTBI) and active pulmonary tuberculosis (PTB) and evaluate the outcome of TB treatment. In this study, we have characterized the changes in the serum metabolic profiles caused by Mycobacterium tuberculosis (Mtb) infection and standard anti-TB treatment with isoniazid–rifampin–pyrazinamide–ethambutol (HRZE) using GC-MS and LC-MS/MS. Seven metabolites, including 3-oxopalmitic acid, akeboside ste, sulfolithocholic acid, 2-decylfuran (4,8,8-trimethyldecahydro-1,4-methanoazulen-9-yl)methanol, d-(+)-camphor, and 2-methylaminoadenosine, were identified to have significantly higher levels in LTBI and untreated PTB patients (T0) than those in uninfected healthy controls (Un). Among them, akeboside Ste and sulfolithocholic acid were significantly decreased in PTB patients with 2-month HRZE (T2) and cured PTB patients with 2-month HRZE followed by 4-month isoniazid-rifampin (HR) (T6). Receiver operator characteristic curve analysis revealed that the combined diagnostic model showed excellent performance for distinguishing LT from T0 and Un. By analyzing the biochemical and disease-related pathways, we observed that the differential metabolites in the serum of LTBI or TB patients, compared to healthy controls, were mainly involved in glutathione metabolism, ascorbate and aldarate metabolism, and porphyrin and chlorophyll metabolism. The metabolites with significant differences between the T0 group and the T6 group were mainly enriched in niacin and nicotinamide metabolism. Our study provided more detailed experimental data for developing laboratory standards for evaluating LTBI and cured PTB.

Latently infected CD

Human Immunodeficiency virus type 1 (HIV-1) relies on host cell metabolism for all aspects of viral replication. Efficient HIV-1 entry, reverse transcription, and integration occurs in activated T cells because HIV-1 proteins co-opt host metabolic pathways to fuel the anabolic requirements of virion production. The HIV-1 viral life cycle is especially dependent on mTOR, which drives signaling and metabolic pathways required for viral entry, replication, and latency. As a central regulator of host cell metabolism, mTOR and its downstream effectors help to regulate the expression of enzymes within the glycolytic and pentose phosphate pathways along with other metabolic pathways regulating amino acid uptake, lipid metabolism, and autophagy. In HIV-1 pathogenesis, mTOR, in addition to HIF-1α and Myc signaling pathways, alter host cell metabolism to create an optimal environment for viral replication. Increased glycolysis and pentose phosphate pathway activity are required in the early stages of the viral life cycle, such as providing sufficient dNTPs for reverse transcription. In later stages, fatty acid synthesis is required for creating cholesterol and membrane lipids required for viral budding. Epigenetics of the provirus fueled by metabolism and mTOR signaling likewise controls active and latent infection. Acetyl-CoA and methyl group abundance, supplied by the TCA cycle and amino acid uptake respectively, may regulate latent infection and reactivation. Thus, understanding and exploring new connections between cellular metabolism and HIV-1 pathogenesis may yield new insights into the latent viral reservoirs and fuel novel treatments and cure strategies.

Summary A higher proportion of CD68-positive tumour associated macrophages (TAMs) has been associated with poorer outcomes in HIV-negative patients with Hodgkin lymphoma (HL), but whether this is true in HIV-positive patients with HL is not known. In this study, we investigated the number of CD68-positive TAMs and expression of programmed cell death-ligand 1 (PD-L1) in lymph node specimens from HL patients and correlated expression with clinical features (HIV status, disease severity and survival) and histopathological features (EBV latent positivity and subtype of HL). We stained archived lymph node specimens from 77 patients diagnosed with HL for CD68 and PD-L1. Stains were graded as: CD68 low (≤25%), CD68 high (>25%), PD-L1 low (≤50%), and PD-L1 high (>50%). Expression levels were correlated with the clinical and histopathological features using bivariate and multivariate analyses. Survival was analysed by overall and progression-free survival. Thirty-four of the 77 included patients (44%) were HIV-positive. EBV latency was detected in 97% of HIV-positive HL patients and in 14% of HIV-negative HL patients. A high CD68 score was associated with lower median haemoglobin levels (9.4 vs 11.4 g/dL; p=0.02), platelet numbers (262 vs 424 cells ×109/L; p=0.01), and lymphocyte numbers (0.99 vs 1.70 cells ×109/L, p=0.01) and a trend towards advanced disease (international prognostic score ≥4; hazard ratio 2.4; confidence interval 0.89–6.47; p=0.08). HIV status did not affect CD68 or PD-L1 expression. A higher proportion of CD68-positive TAMs was found in samples that were EBV-positive. HIV positivity and EBV negativity correlated with poorer survival. CD68 and PD-L1 expression were not predictive of survival. High CD68 expression was associated with EBV positivity but not HIV positivity and did not predict adverse outcomes. PD-L1 expression was unaffected by HIV status or EBV positivity and did predict adverse outcomes.

Herpes simplex virus 1 (HSV-1) is a human pathogen capable of establishing lifelong latent infections that can reactivate under stress conditions. A viral immediate early protein that plays important roles in the HSV-1 lytic and latent infections is the viral E3 ubiquitin ligase, ICP0. ICP0 transactivates all temporal classes of HSV-1 genes and facilitates viral gene expression. ICP0 also impairs the antiviral effects of interferon (IFN)-β, a component of host innate defenses known to limit viral replication. To begin to understand how ICP0 allows HSV-1 to disarm the IFN-β response, we performed genetic analyses using a series of ICP0 truncation mutants in the absence and presence of IFN-β in cell culture. We observed that IFN-β pretreatment of cells significantly impaired the replication of the ICP0 truncation mutants

Epstein-Barr nuclear antigen 1 (EBNA1) is a multifunctional viral-encoded DNA-binding protein essential for Epstein-Barr virus (EBV) DNA replication and episome maintenance. EBNA1 binds to two functionally distinct elements at the viral origin of plasmid replication (oriP), termed the dyad symmetry (DS) element, required for replication initiation and the family of repeats (FR) required for episome maintenance. Here, we determined the cryo-electron microscopy (cryo-EM) structure of the EBNA1 DNA binding domain (DBD) from amino acids (aa) 459 to 614 and its interaction with two tandem sites at the DS and FR. We found that EBNA1 induces a strong DNA bending angle in the DS, while the FR is more linear. The N-terminal arm of the DBD (aa 444 to 468) makes extensive contact with DNA as it wraps around the minor groove, with some conformational variation among EBNA1 monomers. Mutation of variable-contact residues K460 and K461 had only minor effects on DNA binding but had abrogated oriP-dependent DNA replication. We also observed that the AT-rich intervening DNA between EBNA1 binding sites in the FR can be occupied by the EBNA1 AT hook, N-terminal domain (NTD) aa 1 to 90 to form a Zn-dependent stable complex with EBNA1 DBD on a 2×FR DNA template. We propose a model showing EBNA1 DBD and NTD cobinding at the FR and suggest that this may contribute to the oligomerization of viral episomes important for maintenance during latent infection. IMPORTANCE EBV latent infection is causally linked to diverse cancers and autoimmune disorders. EBNA1 is the viral-encoded DNA binding protein required for episomal maintenance during latent infection and is consistently expressed in all EBV tumors. The interaction of EBNA1 with different genetic elements confers different viral functions, such as replication initiation at DS and chromosome tethering at FR. Here, we used cryo-EM to determine the structure of the EBNA1 DNA-binding domain (DBD) bound to two tandem sites at the DS and at the FR. We also show that the NTD of EBNA1 can interact with the AT-rich DNA sequence between tandem EBNA1 DBD binding sites in the FR. These results provide new information on the mechanism of EBNA1 DNA binding at DS and FR and suggest a higher-order oligomeric structure of EBNA1 bound to FR. Our findings have implications for targeting EBNA1 in EBV-associated disease.

Prion diseases are a group of rare, transmissible, and invariably fatal neurodegenerative diseases that affect both humans and animals. The cause of these diseases is misfolding of the prion protein into pathological isoforms called prions. Of all human prion diseases, 10–15% of cases are genetic and the E200K mutation, which causes familial Creutzfeldt-Jakob disease (CJD), is the most prevalent. For both sporadic and genetic disease, it remains uncertain as to how initial protein misfolding is triggered. Prior studies have linked protein misfolding with oxidative stress insults, deregulated interactions with cellular cofactors, and viral infections. Our previous work developed a cerebral organoid (CO) model using human induced pluripotent stem cells containing the E200K mutation. COs are three-dimensional human neural tissues that permit the study of host genetics and environmental factors that contribute to disease onset. Isogenically matched COs with and without the E200K mutation were used to investigate the propensity of E200K PrP to misfold following cellular insults associated with oxidative stress. Since viral infections have also been associated with oxidative stress and neurodegenerative diseases, we additionally investigated the influence of Herpes Simplex Type-1 virus (HSV1), a neurotropic virus that establishes life-long latent infection in its host, on E200K PrP misfolding. While COs proved to be highly infectable with HSV1, neither acute nor latent infection, or direct oxidative stress insult, resulted in evidence of E200K prion misfolding. We conclude that misfolding into seeding-active PrP species is not readily induced by oxidative stress or HSV1 in our organoid system.

Age-associated B cells (ABCs; CD19+CD11c+T-bet+) are a unique population that are increased in an array of viral infections, though their role during latent infection is largely unexplored. Here, we use murine gammaherpesvirus 68 (γHV68) to demonstrate that ABCs remain elevated long-term during latent infection and express IFNγ and TNF. Using a recombinant γHV68 that is cleared following acute infection, we show that ABCs persist in the absence of latent virus, though their expression of IFNγ and TNF is decreased. With a fluorescent reporter gene-expressing γHV68 we demonstrate that ABCs are infected with γHV68 at similar rates to other previously activated B cells. We find that mice without ABCs display defects in anti-viral IgG2a/c antibodies and are more susceptible to reactivation of γHV68 following virus challenges that typically do not break latency. Together, these results indicate that ABCs are a persistent effector subset during latent viral infection that impedes γHV68 reactivation.

Costimulatory interactions can be critical in developing immune responses to infectious agents. We recently reported that herpes simplex type 1 (HSV-1) infections of the cornea require a functional CD28-CD80/86 interaction to not only reduce the likelihood of encephalitis, but also to mediate herpetic stromal keratitis (HSK) following viral reactivation. In this same spirit we decided to determine the role that CD137 costimulation plays during HSK. Using both B6-CD137L-/- mice, as well as antagonistic and agonistic antibodies to CD137 we characterize the immune response and to what extent CD137 plays an important role during this disease. Immune responses were measured in both the cornea and in the trigeminal ganglia where the virus forms a latent infection. We demonstrate that CD137 costimulation leads to reduced corneal disease. Interestingly, we observed that lack of CD137 costimulation resulted in significantly reduced CD8+ T expansion and function in the trigeminal ganglia. Finally, we showed that viruses that have been genetically altered to express CD137 display significantly reduced corneal disease, though they did present similar levels of trigeminal infection and peripheral virus production following reactivation of a latent infection. CD137 interactions lead to reduced HSK and are necessary to develop robust trigeminal CD8+ T cell responses.

Understanding the molecular mechanism of herpes simplex virus type 1 (HSV-1) latent infection and reactivation in neurons requires the use of model systems. However, establishing a quiescent infection in cultured neurons is problematic as infectious virus released from any productively infected neuron can superinfect the cultures. Here, we describe a new reporter virus, HSV-1 Stayput-GFP, that is defective for cell-to-cell spread and can be used to model latency and reactivation at the single neuron level. Importantly, quiescent infection of neurons with Stayput-GFP can be established without the use of a viral DNA replication inhibitor. The establishment of a quiescent state requires a longer time frame than previous models of HSV latency using DNA replication inhibitors. This results in a decreased ability of the virus to reactivate, and the use of multiple reactivation triggers is required. Using this system, we demonstrate that an initial Phase I wave of lytic gene expression occurs independently of histone demethylase activity and viral DNA replication but is dependent on the neuronal cell stress protein, DLK. Progression into the later, Phase II wave of reactivation, characterized by detectable late viral protein synthesis and a requirement for histone demethylase activity, is also observed with the Stayput-GFP model system. These data demonstrate that the two waves of viral gene expression following HSV-1 reactivation are independent of secondary infection and occur when latent infections are established in the absence of a viral DNA replication inhibitor.ImportanceHerpes simplex virus-1 (HSV-1) enters a latent infection in neurons and periodically reactivates. Reactivation manifests as a variety of clinical symptoms. Studying latency and reactivation in vitro is invaluable, allowing the molecular mechanisms behind both processes to be targeted by therapeutics that reduce the clinical consequences. Here, we describe a novel in vitro model system using a cell-to-cell spread defective HSV-1, known as Stayput-GFP, which allows for the study of latency and reactivation at the single neuron level. We anticipate this new model system will be an incredibly valuable tool for studying the establishment and reactivation of HSV-1 latent infection in vitro. Using this model, we find that initial reactivation events are dependent on cellular stress kinase DLK, but independent of histone demethylase activity and viral DNA replication. Our data therefore demonstrate the essential role of DLK in mediating a wave of lytic gene expression unique to reactivation.

Introduction: Understanding whether human papillomavirus (HPV) may establish latency in the uterine cervix is important. A better understanding of HPV natural history is useful for clinical counseling of women attending screening and to accurately inform health prevention strategies such as screening and HPV vaccination. We evaluated the extent of latent HPV infections in older women with a history of abnormal cytology. Material and Methods: We conducted a cross-sectional study in Aarhus, Denmark, from March 2013 through April 2015. Women were enrolled if they underwent cervical amputation or total hysterectomy because of benign disease. Prior to surgery, women completed a questionnaire and a cervical smear was collected for HPV testing and morphological assessment. For evaluation of latency (i.e., no evidence of active HPV infection, but HPV detected in the tissue), we selected women with a history of abnormal cervical cytology or histology, as these women were considered at increased risk of harboring a latent infection. Cervical tissue underwent extensive HPV testing using the SPF10-DEIA-LipA25 assay. Results: Of 103 women enrolled, 26 were included in this analysis. Median age was 55 years (interquartile range [IQR] 52–65), and most women were postmenopausal and parous. The median number of sexual partners over the lifetime was six (IQR 3–10), and 85% reported no recent new sexual partner. Five women (19.2%) had evidence of active infection at the time of surgery, and 19 underwent latency evaluation. Of these, a latent infection was detected in 11 (57.9%), with HPV16 being the most prevalent type (50%). Nearly 80% (n = 14) of the 18 women with a history of previous low-grade or high-grade cytology with no treatment had an active or latent HPV infection, with latent infections predominating. HPV was detected in two of the six women with a history of high-grade cytology and subsequent excisional treatment, both as latent infections. Conclusions: HPV can be detected in cervical tissue specimens without any evidence of an active HPV infection, indicative of a latent, immunologically controlled infection. Modeling studies should consider including a latent state in their model when estimating the appropriate age to stop screening and when evaluating the impact of HPV vaccination.

Background Systemic reactivation of herpesviruses may occur in intensive care unit (ICU) patients and is associated with morbidity and mortality. Data on severe Coronavirus disease-19 (COVID-19) and concomitant reactivation of herpesviruses are lacking. Methods We selected patients admitted to ICU for confirmed COVID-19 who underwent systematic testing for Epstein–Barr virus (EBV), cytomegalovirus (CMV) and human-herpes virus-6 (HHV-6) DNAemia while in the ICU. We retrospectively analysed frequency, timing, duration and co-occurrence of viral DNAemia. Results Thirty-four patients were included. Viremia with EBV, CMV, and HHV-6 was detected in 28 (82%), 5 (15%), and 7 (22%) patients, respectively. EBV reactivation occurred early after ICU admission and was associated with longer ICU length-of-stay. Conclusions While in the ICU, critically ill patients with COVID-19 are prone to develop reactivations due to various types of herpesviruses.

Introduction The new-generation QuantiFERON (QFT)-TB Gold Plus (QFT-Plus) is expected to be useful because it includes a new peptide that is supposed to induce a CD8+ T cell response. There is a need for a new marker with sensitivity higher than that of the conventional IFN-γ release assays owing to false-negative results in the latter. This study aimed to compare cytokines in QFT-plus and QuantiFERON-Gold In-Tube (QFT-GIT) supernatants to discriminate between active tuberculosis and latent tuberculosis infection (LTBI). Methods A cross-sectional study was conducted at Tokyo National Hospital, wherein 21 LTBI patients and age and sex-matched active TB patients were randomly selected. The levels of various cytokines were measured and compared using the MAGPIX System, and receiver operating characteristic (ROC) curves were generated. Results IL-1RA, IFN-γ, CXCL10/IP-10, and CCL4/MIP-1β levels were higher in the active TB group than in the LTBI group in QFT-GIT antigen (GIT Ag) tubes. In QFT-plus tubes, IL-1RA was higher in TB1 and TB2 tubes, while CCL2/MCP-1 was higher only in TB2 tubes. In Nil tubes, CCL5/RANTES, TNF-α, PDGF-BB, and IL-2 levels were significantly higher in the active TB group. IL-1RA in GIT Ag tubes showed the highest area under the curve of 0.8367. The sensitivity and specificity of IL-1RA were 66.7% (95% confidence interval [CI]: 43.0–85.4) and 90.5% (95% CI: 69.6–98.8), respectively, which were the highest among the cytokines. Conclusions IL-1RA level in the QFT-GIT supernatant can be a good marker for discriminating active TB from LTBI.

The cause of most Parkinson's disease cases is unknown. However, it is well documented that mitochondrial dysfunction and misfolded α synuclein aggregation are important cellular abnormalities associated with the disease. In this paper, we use the microcompetition model to show how latent viruses, which infect the central and peripheral nervous systems, can cause the observed mitochondrial dysfunction and excess α synuclein aggregation, and eventually, Parkinson's disease.

Objectives The aim of this retrospective analysis was to assess the incidence of hepatitis B virus (HBV) reactivation among patients with myeloproliferative neoplasms (MPN) during and after ruxolitinib treatment. Methods Between February 2013 and February 2020, 224 patients with MPN were treated using ruxolitinib at Peking Union Medical College Hospital. Of these, 6 had chronic, and 56 had resolved HBV infection, including 43 patients who received combination treatment with thalidomide, prednisone, and stanozolol (TSP) during ruxolitinib treatment. Results Two patients with chronic HBV infection who did not take any antiviral prophylaxis developed HBV reactivation and hepatitis flare. The other four patients with chronic HBV infection, who took antiviral prophylaxis before ruxolitinib treatment, did not develop HBV reactivation. Also, no patients with resolved HBV infection received antiviral prophylaxis and developed HBV reactivation. Conclusion This study demonstrated that HBV reactivation and hepatitis flare might commonly occur a few months after initiating ruxolitinib treatment in patients with chronic HBV infection who did not take antiviral prophylaxis, especially in combination with TSP. Still, it was extremely rare in patients with resolved HBV infection.

In this paper, an HIV infection model with latent infection, Beddington-DeAngelis infection function, B-cell immune response and four time delays is formulated. The well-posedness of the model solution is rigorously derived, and the basic reproduction number $\mathcal{R}_0$ and the B-cell immune response reproduction number $\mathcal{R}_1$ are also obtained. By analyzing the modulus of the characteristic equation and constructing suitable Lyapunov functions, we establish the global asymptotic stability of the uninfected and the B-cell-inactivated equilibria for the four time delays, respectively. Hopf bifurcation occurs at the B-cell-activated equilibrium when the model includes the immune delay, and the B-cell-activated equilibrium is globally asymptotically stable if the model does not include it. Numerical simulations indicate that the increase of the latency delay, the cell infection delay and the virus maturation delay can cause the B-cell-activated equilibrium stabilize, while the increase of the immune delay can cause it destabilize.

Fluoroquinolone-based preventive therapy reduced risk for tuberculosis disease by 65%., In Karachi, Pakistan, a South Asian megacity with a high prevalence of tuberculosis (TB) and low HIV prevalence, we assessed the effectiveness of fluoroquinolone-based preventive therapy for drug-resistant (DR) TB exposure. During February 2016–March 2017, high-risk household contacts of DR TB patients began a 6-month course of preventive therapy with a fluoroquinolone-based, 2-drug regimen. We assessed effectiveness in this cohort by comparing the rate and risk for TB disease over 2 years to the rates and risks reported in the literature. Of 172 participants, TB occurred in 2 persons over 336 person-years of observation. TB disease incidence rate observed in the cohort was 6.0/1,000 person-years. The incidence rate ratio ranged from 0.29 (95% CI 0.04–1.3) to 0.50 (95% CI 0.06–2.8), with a pooled estimate of 0.35 (95% CI 0.14–0.87). Overall, fluoroquinolone-based preventive therapy for DR TB exposure reduced risk for TB disease by 65%.

Introduction: There have been several studies investigating the association between Toxoplasma gondii seropositivity and psychiatric disorders although there is insufficient data on causality. Suicide, depression, and anxiety disorders have been especially investigated in this regard. In this study, we aimed to investigate whether there is any causal association between Toxoplasma gondii seropositivity and suicide attempts in adolescents. Methodology: This is a case-control study conducted between January and December 2019. A total of 27 adolescents who had attempted suicide and were aged between 12 and 18 years were included in the study. 26 age and sex ratio matched healthy volunteers were taken as the control group. A possible association between suicide attempts and Toxoplasma gondii serology (IgM and IgG) was investigated.. Results: The suicide attempt group consisted of 17 females and 10 males. The mean age was 15.9 ± 1.4 (13.5-17.9) years. Toxoplasma gondii IgG seropositivity was 3.7% (1/27) in the suicide attempt group and 3.8% (1/26) in the control group. There was no significant association between the suicide attempt group and the control group in terms of the presence of Toxoplasma gondii IgG antibodies (p > 0.05). Conclusion: Our study is one of the few studies examining the association between Toxoplasma gondii seropositivity and suicide attempts in adolescents yet we did not find any significant association. Further evidence is needed to clarify this controversial issue.

Cytomegalovirus (CMV) remains a significant burden in lung transplant recipients. Deficiencies in T-cell immunity posttransplant increase the risk of CMV-associated complications. However, it is not clear if underlying poor pretransplant immunity increases risk. To assess this, we recruited 39 prospective lung transplant patients and performed QuantiFERON-CMV on their peripheral blood. More than a third of prospective CMV-seropositive transplant recipients were CMV non-immune reactive (CMV-NIR) pretransplant. CMV-NIR status was associated with a significantly higher incidence of CMV reactivation posttransplant, demonstrating that dysfunctional CMV immunity in prospective lung transplant recipients is associated with an increased risk of viral reactivation posttransplant.

Morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT) are still essentially affected by reactivation of cytomegalovirus (CMV). We evaluated 80 seropositive patients transplanted consecutively between March 2018 and March 2019 who received letermovir (LET) prophylaxis from engraftment until day +100 and retrospectively compared them with 80 patients without LET allografted between January 2017 and March 2018. The primary endpoint of this study was the cumulative incidence (CI) of clinically significant CMV infection (CS-CMVi) defined as CMV reactivation demanding preemptive treatment or CMV disease. With 14% CI of CS-CMVi at day +100 (11 events) was significantly lower in the LET cohort when compared to the control group (33 events, 41%; HR 0.29; p p = 0.002). One-year overall survival was 72% in the control arm vs 84% in the LET arm (HR 0.75 [95%CI 0.43–1.30]; p

Traditionally, the protozoan parasite Toxoplasma gondii has been thought of as relevant to public health primarily within the context of congenital toxoplasmosis or postnatally acquired disease in immunocompromised patients. However, latent T. gondii infection has been increasingly associated with a wide variety of neuropsychiatric disorders and, more recently, causal frameworks for these epidemiological associations have been proposed. We present assimilated evidence on the associations between T. gondii and various human neuropsychiatric disorders and outline how these may be explained within a unifying causal framework. We argue that the occult effects of latent T. gondii infection likely outweigh the recognised overt morbidity caused by toxoplasmosis, substantially raising the public health importance of this parasite.

Many successful pathogens cause latent infections, remaining dormant within the host for years but retaining the ability to reactivate to cause symptomatic disease. The human opportunistic fungal pathogen Cryptococcus neoformans establishes latent pulmonary infections in immunocompetent individuals upon inhalation from the environment. These latent infections are frequently characterized by granulomas, or foci of chronic inflammation, that contain dormant and persistent cryptococcal cells. Immunosuppression can cause these granulomas to break down and release fungal cells that proliferate, disseminate, and eventually cause lethal cryptococcosis. This course of fungal latency and reactivation is understudied due to limited models, as chronic pulmonary granulomas do not typically form in mouse cryptococcal infections. A loss-of-function mutation in the Cryptococcus-specific

Herpesviruses are ubiquitous human pathogens. After productive (lytic) infection, all human herpesviruses are able to establish life-long latent infection and reactivate from it. Latent infection entails suppression of viral replication, maintenance of the viral genome in infected cells, and the ability to reactivate. Most human herpesviruses encode microRNAs (miRNAs) that regulate these processes during latency. Meanwhile, cellular miRNAs are hijacked by herpesviruses to participate in these processes. The viral or cellular miRNAs either directly target viral transcripts or indirectly affect viral infection through host pathways. These findings shed light on the molecular determinants that control the lytic-latent switch and may lead to novel therapeutics targeting latent infection. We discuss the multiple mechanisms by which miRNAs regulate herpesvirus latency, focusing on the patterns in these mechanisms.

Electrode migration is one of the most common complication of Spinal Cord Stimulation (SCS). Usually the lead migrates cranio-caudally or laterally and in the vast majority of cases occurs during the first few months after implantation. One method of preventing lead migration is the use of open-surgical insertion of paddle electrodes.51-year old woman was admitted for a revision of postoperative wound after implantation of Spinal Cord Stimulator, which was inserted 4 years earlier due to Failed Back Surgery Syndrome (FBSS). Two years after surgery the patient reported severe pain at the site of electrode implantation. After removal of scar tissue pulling on electrode wires the symptoms subsided. In the following months impaired healing of the postoperative wound was observed. For a long time, the patient would not consent to removal of SCS hardware because of good therapeutic effect. When she was finally admitted for surgery, radiological examination demonstrated significant electrode migration out of the vertebral canal. Surgery was performed to remove all of the hardware.In this case, electrode migration out of the vertebral canal resulted from prolonged infection of SCS hardware. The importance of an infection prevention in neuromodulation procedures should be highlighted. According to our best knowledge, this is the first presented case of paddle type electrode extraspinal migration.

OBJECTIVE. Cytomegalovirus (CMV) and Toxoplasma gondii are organisms that may infect the brain and have cognitive and behavioral consequences. We hypothesized that these latent infections would be prospectively associated with poorer cognition and more problems in self-regulation among older adults. METHODS. Older adults (N = 138, M(age) = 75.5 years, 59% women) had CMV and T. gondii serostatus tested, crystallized intelligence estimated (North American Adult Reading Test), and executive function (EF, e.g., Trail Making Test) and self-regulation (Behavior Regulation Inventory of Executive Function - Adult) assessed in visits occurring every six months (M(visits) = 16). RESULTS. CMV+ people (79%) had significantly poorer self-regulation vs. CMV− people (21%) (Behavioral Regulation: γ = 0.108, 95% CI [0.009,0.206]; Metacognition: γ = 0.117, 95% CI [0.005,0.229]), but not intelligence or EF. T. gondii+ people (24%) were not significantly different from T. gondii− people (76%) on any outcome. However, T. gondii+ men had better self-regulation vs. T. gondii− men, and the opposite was true of women (Behavioral Regulation interaction γ = 0.267, 95% CI [0.093, 0.441]). CONCLUSIONS. CMV latent infection was associated with more problems in self-regulation, and the magnitude of this difference was clinically significant. T. gondii latent infection was associated with more problems, but only for women. Latent infection might associate with self-regulation but not EF because of factors influencing self-regulation but not neuropsychological test performance, such as values and emotion. Efforts to link latent infection with executive functions might in future include the application of those functions to self-regulation in daily life.

Equine herpesvirus-1 (EHV-1) can affect the entire equine sector in EU, and the large outbreak reported in 2021 in Spain drew attention to the needs of the European Commission for scientific advice for the assessment of EHV-1 infection within the framework of Animal Health Law. EHV-1 is considered endemic in the EU; its main risk is linked to the characteristic of producing latent life-long infections. These can reactivate producing clinical disease, which can include respiratory, abortive and possibly fatal neurological forms. From the epidemiological and genomic viewpoint, there are no specific neuropathogenic EHV-1 strains; the respiratory, reproductive and neurological signs are not found to be strain-specific. This was also the case of the virus that caused the outbreak in Valencia (Spain) in 2021, which was genetically closely related to other viruses circulating before in Europe, and did not present the so-called neuropathogenic genotype. The outbreak reported in Valencia was followed by wide geographic spread of the virus possibly due to a delay in diagnosis and late application of biosecurity measures. The recommended and most sensitive diagnostic test for detecting EHV-1 is PCR performed on swabs collected according to the type of clinical signs. Serological assays on paired blood samples can help to detect a recent infection, while no diagnostic methods are available to detect EHV-1 latent infections. Safe movements of horses can be ensured at premovement phase by testing and issuing health certificates, and by isolating animals upon arrival at new premises with regular health monitoring. In case of suspicion, movements should be forbidden and EHV-1 infection early detected/confirmed by validated diagnostic tools. During outbreaks, no movements should be allowed until 21?days after the detection of the last case. In general, vaccination against EHV-1 should be promoted, although this offers limited protection against the neurological form of the disease.

Despite the clinical importance of latent human immunodeficiency virus type 1 (HIV-1) infection, our understanding of the biomolecular processes involved in HIV-1 latency control is still limited. This study was designed to address whether interactions between viral proteins, specifically HIV Nef, and the host cell could affect latency establishment. The study was driven by three reported observations. First, early reports suggested that human immunodeficiency virus type 2 (HIV-2) infection in patients produces a lower viral RNA/DNA ratio than HIV-1 infection, potentially indicating an increased propensity of HIV-2 to produce latent infection. Second, Nef, an early viral gene product, has been shown to alter the activation state of infected cells in a lentiviral lineage-dependent manner. Third, it has been demonstrated that the ability of HIV-1 to establish latent infection is a function of the activation state of the host cell at the time of infection. Based on these observations, we reasoned that HIV-2 Nef may have the ability to promote latency establishment. We demonstrate that HIV-1 latency establishment in T cell lines and primary T cells is indeed differentially modulated by Nef proteins. In the context of an HIV-1 backbone, HIV-1 Nef promoted active HIV-1 infection, while HIV-2 Nef strongly promoted latency establishment. Given that Nef represents the only difference in these HIV-1 vectors and is known to interact with numerous cellular factors, these data add support to the idea that latency establishment is a host cell-virus interaction phenomenon, but they also suggest that the HIV-1 lineage may have evolved mechanisms to counteract host cell suppression. IMPORTANCE Therapeutic attempts to eliminate the latent HIV-1 reservoir have failed, at least in part due to our incomplete biomolecular understanding of how latent HIV-1 infection is established and maintained. We here address the fundamental question of whether all lentiviruses actually possess a similar capacity to establish latent infections or whether there are differences between the lentiviral lineages driving differential latency establishment that could be exploited to develop improved latency reversal agents. Research investigating the viral RNA/DNA ratio in HIV-1 and HIV-2 patients could suggest that HIV-2 indeed has a much higher propensity to establish latent infections, a trait that we found, at least in part, to be attributable to the HIV-2 Nef protein. Reported Nef-mediated effects on host cell activation thus also affect latency establishment, and HIV-1 vectors that carry different lentiviral nef genes should become key tools to develop a better understanding of the biomolecular basis of HIV-1 latency establishment.

Purpose To report two cases of herpes simplex virus keratitis reactivation following Pfizer-BioNTech COVID-19 (BNT162b2) mRNA vaccination. Methods Two patients (one male, age 42 years, and one female, age 29 years) who are known to have herpetic keratitis presented to our emergency room in a time frame between 4 days and 4 weeks of receiving the vaccine. One patient presented with necrotizing stromal keratitis; the other presented with endotheliitis and epithelial keratitis. PCR for herpes simplex virus (HSV) was obtained from the two patients, and all cases received systemic acyclovir. Results PCR for HSV came positive in both cases. Patients responded well to the provided treatment. Conclusion Ocular herpetic infection may be activated by COVID-19 (BNT162b2) mRNA vaccine. Treating physician should be alert to such associations, and patients should be followed closely. No direct causality has been proven, but further reporting and investigating similar conditions is recommended.

Across the fields of virology and neuroscience, the role of neurotropic viruses in Alzheimer’s disease (AD) has received renewed enthusiasm, with a particular focus on human herpesviruses (HHVs). Recent genomic analyses of brain tissue collections and investigations of the antimicrobial responses of amyloid-β do not exclude a role of HHVs in contributing to or accelerating AD pathogenesis. Due to continued expansion in our aging cohort and the lack of effective treatments for AD, this composition examines a potential neuroviral theory of AD in light of these recent data. Consideration reveals a possible viral “Hit-and-Run” scenario of AD, as well as neurobiological mechanisms (i.e., neuroinflammation, protein quality control, oxidative stress) that may increase risk for AD following neurotropic infection. Although limitations exist, this theoretical framework reveals several novel therapeutic targets that may prove efficacious in AD.

Aims/hypothesis Numerous clinical studies have investigated the anti-CD3ɛ monoclonal antibody otelixizumab in individuals with type 1 diabetes, but limited progress has been made in identifying the optimal clinical dose with acceptable tolerability and safety. The aim of this study was to evaluate the association between dose–response, safety and tolerability, beta cell function preservation and the immunological effects of otelixizumab in new-onset type 1 diabetes. Methods In this randomised, single-blind, placebo-controlled, 24 month study, conducted in five centres in Belgium via the Belgian Diabetes Registry, participants (16–27 years old, n = 40). Randomisation to treatment was by a central computer system; only participants and bedside study personnel were blinded to study treatment. The co-primary endpoints were the incidence of adverse events, the rate of Epstein–Barr virus (EBV) reactivation, and laboratory measures and vital signs. A mixed-meal tolerance test was used to assess beta cell function; exploratory biomarkers were used to measure T cell responses. Results Thirty participants were randomised/28 were analysed (placebo, n = 6/5; otelixizumab 9 mg, n = 9/8; otelixizumab 18 mg, n = 8/8; otelixizumab 27 mg, n = 7/7; otelixizumab 36 mg, n = 0). Dosing was stopped at otelixizumab 27 mg as the predefined EBV reactivation stopping criteria were met. Adverse event frequency and severity were dose dependent; all participants on otelixizumab experienced at least one adverse event related to cytokine release syndrome during the dosing period. EBV reactivation (otelixizumab 9 mg, n = 2/9; 18 mg, n = 4/8: 27 mg, n = 5/7) and clinical manifestations (otelixizumab 9 mg, n = 0/9; 18 mg, n = 1/8; 27 mg, n = 3/7) were rapid, dose dependent and transient, and were associated with increased productive T cell clonality that diminished over time. Change from baseline mixed-meal tolerance test C-peptide weighted mean AUC0–120 min following otelixizumab 9 mg was above baseline for up to 18 months (difference from placebo 0.39 [95% CI 0.06, 0.72]; p = 0.023); no beta cell function preservation was observed at otelixizumab 18 and 27 mg. Conclusions/interpretation A metabolic response was observed with otelixizumab 9 mg, while doses higher than 18 mg increased the risk of unwanted clinical EBV reactivation. Although otelixizumab can temporarily compromise immunocompetence, allowing EBV to reactivate, the effect is dose dependent and transient, as evidenced by a rapid emergence of EBV-specific T cells preceding long-term control over EBV reactivation. Trial registration ClinicalTrials.gov NCT02000817. Funding The study was funded by GlaxoSmithKline.

Objectives This study evaluated the efficacy of the following interferon (IFN)-γ release assays (IGRAs): QuantiFERON-TB Gold Plus (QFT-Plus), QFT-Gold In-Tube (QFT-GIT), and T-SPOT. TB (T-SPOT) with the quantitative values of IFN-γ response. Methods Blood samples were collected from patients with active tuberculosis (TB), latent TB infection (LTBI), individuals with previous TB infection, and healthy volunteers enrolled between May 2017 and June 2018. Results IGRAs results were analyzed in 175 subjects (76 had active TB, 14 had LTBI, 35 had prior TB infection, and 50 were healthy). QFT-Plus and QFT-GIT revealed equal efficacy for IFN-γ values, and the IFN-γ response in QFTs tended to increase with the spot counts in T-SPOT, with similar high sensitivities (approximately 90%) in the active TB group. The test concordance of two of three IGRAs was optimal among all subjects (κ coefficients: 0.82–0.96). Additionally, the median quantitative values of IFN-γ with QFT-Plus and QFT-GIT were higher in the active TB group than in the LTBI and previous TB groups. Conclusion Three IGRAs showed equivalent efficacy with high sensitivities and higher IFN-γ response in active TB group than that in non-active TB group.