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Background: A vaccine against Trypanosoma cruzi, the agent of Chagas disease, would be an excellent additional tool for disease control. A recombinant vaccine based on Tc24 and TSA1 parasite antigens was found to be safe and immunogenic in naïve macaques. Methods: We used RNA-sequencing and performed a transcriptomic analysis of PBMC responses to vaccination of naïve macaques after each vaccine dose, to shed light on the immunogenicity of this vaccine and guide the optimization of doses and formulation. We identified differentially expressed genes and pathways and characterized immunoglobulin and T cell receptor repertoires. Results: RNA-sequencing analysis indicated a clear transcriptomic response of PBMCs after three vaccine doses, with the up-regulation of several immune cell activation pathways and a broad non-polarized immune profile. Analysis of the IgG repertoire showed that it had a rapid turnover with novel IgGs produced following each vaccine dose, while the TCR repertoire presented several persisting clones that were expanded after each vaccine dose. Conclusions: These data suggest that three vaccine doses may be needed for optimum immunogenicity and support the further evaluation of the protective efficacy of this vaccine. [ABSTRACT FROM AUTHOR]

Chagas disease by Trypanosoma cruzi (T. cruzi) infection is a leading cause of myocarditis worldwide. Chagas cardiomyopathy is presented with a wide variety of conduction abnormalities including arrhythmias, first- and second-degree atrioventricular blockade, left ventricular systolic dysfunction and some cases heart failure leading to the death. Currently, there are no effective treatments available against advanced Chagas disease. With the advance in the development of novel therapies, it is important to utilize an animal model that can effectively replicate the diverse stages of Chagas disease, including chronic asymptomatic and symptomatic infection, that are akin to those observed in humans. Therefore, to characterize the cardiac alterations during the evolution of the infection, we evaluated the progression of cardiomyopathy caused by T. cruzi H1 infection in both BALB/c and ICR mouse models by performing electrocardiogram (ECG) studies in unanesthetized mice every month until 210 days post-infection (dpi). In the late chronic phase of infection, we also performed echocardiogram (ECHO) studies to further assess cardiac function. In conclusion, we demonstrated that ICR mice were more susceptible to cardiac alterations compared to BALB/c mice and both mouse strains are suitable experimental models to study chronic T. cruzi infection and novel treatments. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to molecularly characterize Mexican isolates of T. cruzi obtained from infected triatomine bugs (the vectors of T. cruzi) and to evaluate their susceptibility to Nifurtimox (NFX). Methods: Three isolates obtained from Triatoma dimidiata (collected in the State of Veracruz) and one isolate obtained from Triatoma bassolsae (collected in the State of Puebla) were molecularly characterized and the expression of genes associated with natural resistance to NFX was analyzed by qPCR. Results: Molecular characterization by PCR showed that isolates Zn3, Zn5, and SRB1 belong to the DTU TcI, while isolate Sum3 belongs to TcIV. The latter was also confirmed by sequencing of mitochondrial genes. Isolate Zn5 was the most sensitive to treatment with NFX (IC50, 6.8 μM), isolates SRB1 and Zn3 were partially resistant (IC50, 12.8 μM and 12.7 μM) and isolate Sum3 showed a high degree of resistance to NFX (IC50, 21.4 µM). We also found an association between decreased NTR1 or OYE gene expression with NFX resistance. Conclusion: Our results also evidenced a high variability in the susceptibility to NFX of these T. cruzi isolates Central and Southeastern Mexico, suggesting the presence of naturally resistant isolates circulating in the country. These results have important implications for defining treatment policies for patients with Chagas disease. [ABSTRACT FROM AUTHOR]

Introduction: Three decades of evidence have demonstrated that plants are an affordable platform for biopharmaceutical production and delivery. For instance, several plant-made recombinant proteins have been approved for commercialization under good manufacturing practice (GMP). Thus far, plant-based vaccine prototypes have been evaluated at pre- and clinical levels. Particularly, plant-made vaccines against parasitic diseases, such as malaria, cysticercosis, and toxoplasmosis have been successfully produced and orally delivered with promising outcomes in terms of immunogenicity and protection. The experience on several approaches and technical strategies over 30 years accounts for their potential low-cost, high scalability, and easy administration. Areas covered: This platform is an open technology to fight against Chagas disease, one of the most important neglected tropical diseases worldwide. Expert opinion: This review provides a perspective for the potential use of plants as a production platform and delivery system of Trypanosoma cruzi recombinant antigens, analyzing the advantages and limitations with respect to plant-made vaccines produced for other parasitic diseases. Plant-made vaccines are envisioned to fight against Chagas disease and other neglected tropical diseases in those countries suffering endemic prevalence. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi-associated megaesophagus was diagnosed in a domestic Louisiana-born llama with no significant travel history. The llama resided in the same rural area of greater New Orleans, Louisiana, where the first human autochthonous case of Chagas disease was identified in the state. Venous blood from the llama tested positive for T. cruzi kinetoplastid DNA by conventional PCR. The cardiac evaluation was unremarkable, while thoracic radiographs revealed generalized megaesophagus. The llama received supportive care, but was ultimately humanely euthanized. The esophagus was severely distended throughout its length on necropsy, and histologic evaluation showed no microscopic changes in esophageal tissue and minimal to mild lymphoplasmacytic inflammation in cardiac tissue. T. cruzi DNA was detected by conventional PCR in the esophagus, small intestine, and blood despite no protozoan organisms being observed in multiple tissue sections examined. This report contributes to the growing body of evidence of local transmission of T. cruzi in the southern United States, and Chagas disease should be considered a differential diagnosis when evaluating llamas and other large animal species for esophageal dysfunction. There is little research describing megaesophagus or Chagas disease in llamas, and this report aims to increase awareness about this zoonotic disease that is becoming more frequently reported in the southern United States. [ABSTRACT FROM AUTHOR]

Purpose: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a vector-borne disease with a major disease burden in the Americas, with over 6 million cases. There are about 200,000 cases in Ecuador, but the epidemiology of the disease is poorly understood, particularly in the Amazon region, making surveillance and control challenging. Methods: We determined here the seroprevalence of T. cruzi antibodies in a cohort of 516 schoolchildren aged 5–15 years from Chontapunta parish, in the Napo province, Ecuador, using ELISA and indirect hemaglutination tests. Results: We detected a seroprevalence of 0.77% (95% confidence interval 0.31–1.97%), with some significant variation among the three studied communities. Conclusion: These data provide evidence of the ongoing transmission of T. cruzi in this area, and support the need to strengthen epidemiological surveillance and patient care. [ABSTRACT FROM AUTHOR]

Objective: To analyse the ecological and social factors involved in infestation of houses by Triatomadimidiata in a rural locality of Veracruz, Mexico, where active transmission of the parasite is occurring. Methods: A survey was applied to the households of the locality to obtain sociodemographic data. In parallel, T. dimidiata insects were collected during one year through community participation. Using PCR, the insects were genotyped, their infection status was assessed, and parasite genotypes infecting the insects were identified. The vector's blood meal sources were identified using a polymerase–heteroduplex chain reaction assay. Results: Seasonal variations in the patterns of infestation by T. dimidiata were observed. An overall infestation rate of 19.46%, a colonisation index of 9.09%, a dispersion rate of 22.15% and a synanthropy index of 80.6% were found. The collected insects were identified as ITS‐2 group 2 insects, and a natural infection with T. cruzi of 54.35% was found. TcI and no‐TcI genotypes of T. cruzi were found in infected insects. Factors such as rain (P = 0.0006) and temperature (P < 0.0001) were associated with infestation. Analysis of the blood meal sources indicated frequent feeding upon humans and mice. Furthermore, house materials and peridomiciles were found to play an important role in the dynamics of infestation. Conclusions: The contribution of this study is important for understanding the epidemiology of Chagas disease in rural areas of the state of Veracruz and will help to the establishment of an entomological surveillance system and implementation of prevention and control measures in accordance with the reality of the area. [ABSTRACT FROM AUTHOR]

Chagas disease remains a major neglected disease in Colombia. We aimed to characterize Trypanosoma cruzi transmission networks in the Sierra Nevada de Santa Marta (SNSM) region, to shed light on disease ecology and help optimize control strategies. Triatomines were collected in rural communities and analyzed for blood feeding sources, parasite diversity and gut microbiota composition through a metagenomic and deep sequencing approach. Triatoma dimidiata predominated, followed by Rhodnius prolixus, Triatoma maculata, Rhodnius pallescens, Panstrongylus geniculatus and Eratyrus cuspidatus. Twenty-two species were identified as blood sources, resulting in an integrated transmission network with extensive connectivity among sylvatic and domestic host species. Only TcI parasites were detected, predominantly from TcIb but TcIa was also reported. The close relatedness of T. cruzi strains further supported the lack of separate transmission cycles according to habitats or triatomine species. Triatomine microbiota varied according to species, developmental stage and T. cruzi infection. Bacterial families correlated with the presence/absence of T. cruzi were identified. In conclusion, we identified a domestic transmission cycle encompassing multiple vector species and tightly connected with sylvatic hosts in the SNSM region, rather than an isolated domestic transmission cycle. Therefore, integrated interventions targeting all vector species and their contact with humans should be considered. [ABSTRACT FROM AUTHOR]

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Trypanosoma cruzi is a zoonotic parasite endemic in the southern US and the Americas, which may frequently infect dogs, but limited information is available about infections in cats. We surveyed a convenience sample of 284 shelter cats from Southern Louisiana to evaluate T. cruzi infection using serological and PCR tests. Parasites from PCR positive cats were also genotyped by PCR and deep sequencing to assess their genetic diversity. We detected a seropositivity rate for T. cruzi of at least 7.3% (17/234), and 24.6% of cats (70/284) were PCR positive for the parasite. Seropositivity increased with cat age (R2 = 0.91, P = 0.011), corresponding to an incidence of 7.2% ± 1.3 per year, while PCR positivity decreased with age (R2 = 0.93, P = 0.007). Cats were predominantly infected with parasites from TcI and TcVI DTUs, and to a lesser extent from TcIV and TcV DTUs, in agreement with the circulation of these parasite DTUs in local transmission cycles. These results indicate that veterinarians should have a greater awareness of T. cruzi infection in pets and that it would be important to better evaluate the risk for spillover infections in humans. [ABSTRACT FROM AUTHOR]

Background: Chagas disease is a neglected zoonosis of growing concern in the southern US, caused by the parasite Trypanosoma cruzi. We genotyped parasites in a large cohort of PCR positive dogs to shed light on parasite transmission cycles and assess potential relationships between parasite diversity and serological test performance. Methodology/principal findings: We used a metabarcoding approach based on deep sequencing of T. cruzi mini-exon marker to assess parasite diversity. Phylogenetic analysis of 178 sequences from 39 dogs confirmed the presence of T. cruzi discrete typing unit (DTU) TcI and TcIV, as well as TcII, TcV and TcVI for the first time in US dogs. Infections with multiple DTUs occurred in 38% of the dogs. These data indicate a greater genetic diversity of T. cruzi than previously detected in the US. Comparison of T. cruzi sequence diversity indicated that highly similar T. cruzi strains from these DTUs circulate in hosts and vectors in Louisiana, indicating that they are involved in a shared T. cruzi parasite transmission cycle. However, TcIV and TcV were sampled more frequently in vectors, while TcII and TcVI were sampled more frequently in dogs. Conclusions/significance: These observations point to ecological host-fitting being a dominant mechanism involved in the diversification of T. cruzi-host associations. Dogs with negative, discordant or confirmed positive T. cruzi serology harbored TcI parasites with different mini-exon sequences, which strongly supports the hypothesis that parasite genetic diversity is a key factor affecting serological test performance. Thus, the identification of conserved parasite antigens should be a high priority for the improvement of current serological tests. Author summary: Chagas disease is a neglected zoonosis of growing concern in the southern US, caused by the parasite Trypanosoma cruzi. Here we analyzed the parasite genetic diversity in a large cohort of infected dogs to better understand parasite transmission cycles and assess potential relationships between parasite diversity and serological test performance. We used DNA sequencing of a well characterized T. cruzi genetic marker to assess parasite diversity. We confirmed the presence of T. cruzi lineages TcI and TcIV, and report TcII, TcV and TcVI for the first time in US dogs. Parasite lineages TcIV TcII and TcVI appeared more frequent in dogs compared to insect vectors. Dogs with negative, discordant or confirmed positive T. cruzi serology harbored genetically different TcI parasites, which shows that parasite genetic diversity is a key factor affecting serological test performance. Thus, the identification of parasite antigens conserved across strains and lineages should be a high priority for the improvement of current serological tests. [ABSTRACT FROM AUTHOR]

Introduction: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a major public health problem in the Americas, and existing drugs have severe limitations. In this context, a vaccine would be an attractive alternative for disease control. One of the difficulties in developing an effective vaccine lies in the high genetic diversity of T. cruzi. In this study, we evaluated the level of sequence diversity of the leading vaccine candidate Tc24 in multiple parasite strains. Methods and Results: We quantified its level of polymorphism within and between T. cruzi discrete typing units (DTUs) and how this potential polymorphism is structured by different selective pressures. We observed a low level of polymorphism of Tc24 protein, weakly associated with parasite DTUs, but not with the geographic origin of the strains. In particular, Tc24 was under strong purifying selection pressure and predicted CD8+ T‐cell epitopes were mostly conserved. Tc24 strong conservation may be associated with structural/functional constrains to preserve EF hand domains and their calcium‐binding loops, and Tc24 is likely important for the parasite fitness. Discussion: Together, these results show that a vaccine based on Tc24 is likely to be effective against a wide diversity of parasite strains across the American continent, and further development of this vaccine candidate should be a high priority. [ABSTRACT FROM AUTHOR]

Integrating how biodiversity and infectious disease dynamics are linked at multiple levels and scales is highly challenging. Chagas disease is a vector‐borne disease, with specificities of the triatomine vectors and Trypanosoma cruzi parasite life histories resulting in a complex multihost and multistrain life cycle. Here, we tested the hypothesis that T. cruzi transmission cycles are shaped by triatomine host communities and gut microbiota composition by comparing the integrated interactions of Triatoma sanguisuga in southern Louisiana with feeding hosts, T. cruzi parasite and bacterial microbiota in two habitats. Bugs were collected from resident's houses and animal shelters and analysed for genetic structure, blood feeding sources, T. cruzi parasites, and bacterial diversity by PCR amplification of specific DNA markers followed by next‐generation sequencing, in an integrative metabarcoding approach. T. sanguisuga feeding host communities appeared opportunistic and defined by host abundance in each habitat, yielding distinct parasite transmission networks among hosts. The circulation of a large diversity of T. cruzi DTUs was also detected, with TcII and TcV detected for the first time in triatomines in the US. The bacterial microbiota was highly diverse and varied significantly according to the DTU infecting the bugs, indicating specific interactions among them in the gut. Expanding such studies to multiple habitats and additional triatomine species would be key to further refine our understanding of the complex life cycles of multihost, multistrain parasites such as T. cruzi, and may lead to improved disease control strategies. [ABSTRACT FROM AUTHOR]

Purpose: The state of Veracruz, Mexico, is a well-recognized endemic region for Chagas disease, but congenital transmission has not been extensively studied. We estimated here the prevalence and the risk of congenital transmission of Trypanosoma cruzi in pregnant women from 27 municipalities of central Veracruz. Methods: 528 sera from pregnant women were analyzed by ELISA and IFA assays for the detection of IgG antibodies against T. cruzi. Results: The presence of anti-T. cruzi antibodies was identified in women from 17 municipalities, obtaining an overall seroprevalence of 17.0%. A higher seropositivity was observed in the municipalities of Orizaba (25.2%), Nogales (13.6%), and Río Blanco (10.5%). The results suggest that there is a high risk of congenital transmission of T. cruzi in the region. Conclusion: There are currently limited actions for the surveillance and control of congenital transmission of Chagas disease in Veracruz. [ABSTRACT FROM AUTHOR]

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi is one of the most important neglected parasitic diseases in the Americas. Vaccines represent an attractive complementary strategy for the control of T. cruzi infection and pre-clinical studies in mice demonstrated that trypomastigote surface antigen (TSA-1) and the flagellar calcium-binding (Tc24) parasite antigens are promising candidates for vaccine development. We performed here the first evaluation of the safety and immunogenicity of two recombinant vaccine antigens (named TSA1-C4 and Tc24-C4) in naïve non-human primates. Three rhesus macaques received 3 doses of each recombinant protein, formulated with E6020 (Eisai Co., Ltd.), a novel Toll-like receptor-4 agonist, in a stable emulsion. All parameters from blood chemistry and blood cell counts were stable over the course of the study and unaffected by the vaccine. A specific IgG response against both antigens was detectable after the first vaccine dose, and increased with the second dose. After three vaccine doses, stimulation of PBMCs with a peptide pool derived from TSA1-C4 resulted in the induction of TSA1-C4-specific TNFα-, IL-2- and IFNγ-producing CD4+ in one or two animals while stimulation with a peptide pool derived from Tc24-C4 only activated IFNγ-producing CD4+T cells in one animal. In two animals there was also activation of TSA1-C4-specific IL2-producing CD8+ T cells. This is the first report of the immunogenicity of T. cruzi- derived recombinant antigens formulated as an emulsion with a TLR4 agonist in a non-human primate model. Our results strongly support the need for further evaluation of the preventive efficacy of this type of vaccine in non-human primates and explore the effect of the vaccine in a therapeutic model of naturally-infected Chagasic non-human primates, which would strengthen the rationale for the clinical development as a human vaccine against Chagas disease. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi is the causative agent of Chagas disease, a Neglected Tropical Disease affecting 8 million people in the Americas. Triatomine hematophagous vectors feed on a high diversity of vertebrate species that can be reservoirs or dead-end hosts, such as avian species refractory to T. cruzi. To understand its transmission dynamics in synanthropic and domesticated species living within villages is essential to quantify disease risk and assess the potential of zooprophylaxis. We developed a SI model of T. cruzi transmission in a multi-host community where vector reproduction and parasite transmission depend on a triatomine blood-feeding rate accounting for vector host preferences and interference while feeding. The model was parameterized to describe T. cruzi transmission in villages of the Yucatan peninsula, Mexico, using the information about Triatoma dimidiata vectors and host populations accumulated over the past 15 years. Extensive analyses of the model showed that dogs are key reservoirs and contributors to human infection, as compared to synanthropic rodents and cats, while chickens or other domesticated avian hosts dilute T. cruzi transmission despite increasing vector abundance. In this context, reducing the number of dogs or increasing avian hosts abundance decreases incidence in humans by up to 56% and 39%, respectively, while combining such changes reduces incidence by 71%. Although such effects are only reached over >10-years periods, they represent important considerations to be included in the design of cost-effective Integrated Vector Management. The concomitant reduction in T. cruzi vector prevalence estimated by simulating these zooprophylactic interventions could indeed complement the removal of colonies from the peridomiciles or the use of insect screens that lower vector indoor abundance by ~60% and ~80%. These new findings reinforce the idea that education and community empowerment to reduce basic risk factors is a cornerstone to reach and sustain the key objective of interrupting Chagas disease intra-domiciliary transmission. Author summary: 'Chagas disease' (CD) is a Neglected Tropical Disease endemic in 21 American countries that is caused by a parasite, Trypanosoma cruzi, transmitted to vertebrates including humans by triatomine bugs. The main strategy to restrain CD burden consists of spraying insecticides in human dwellings. However, vector control failures and emerging insecticide resistance require complementing strategies. One such strategy could be to change the human associated host community so that the abundance of parasite 'reservoirs' decreases and those of parasite 'dead-ends' increases. This requires careful quantitative evaluation using specifically tailored mathematical models. By doing so, we showed that reducing the abundance of reservoir dogs and increasing those of avian hosts that cannot be infected by T. cruzi can lower new human infections by up to 56% and 39%. Although such effects take time to manifest themselves, our results suggest that 'zooprophylaxis' can be part of an integrated and sustainable disease management. [ABSTRACT FROM AUTHOR]

Background: Chagas disease is a zoonotic disease caused by the protozoan parasite Trypanosoma cruzi. The role of dogs as sentinels has been proposed in multiple regions, as they are a domestic reservoir for T. cruzi. Our objective was to determine the prevalence of T. cruzi infection in shelter dogs from southern Louisiana, and assess its magnitude and distribution. Results: A total of 540 dogs were enrolled, from 20 animal shelters, and tested for T. cruzi infection by serological tests (rapid test, ELISA and western blot) and PCR. We documented a high prevalence of T. cruzi infection with at least 6.9% (95% CI: 5.0–9.3%) seropositive and 15.7% (95% CI: 12.9–19.1%) PCR-positive dogs. Serological tests showed limited agreement, and concordance between serology and PCR was higher when considering reactivity to single serological tests. Trypanosoma cruzi infection was distributed evenly among shelters. Infection was significantly correlated with age (R2 = 0.99), indicating an incidence of new cases of 2.27 ± 0.25% per year. Conclusion: Trypanosoma cruzi infection is a significant and widespread veterinary problem in shelter dogs in the region, although it is mostly unnoticed by health professionals. This highlights the need for greater awareness of T. cruzi infection among the veterinary community and dog owners. [ABSTRACT FROM AUTHOR]

Background Trypanosoma cruzi is a zoonotic pathogen of increasing relevance in the USA, with a growing number of autochthonous cases identified in recent years. The identification of parasite genotypes is key to understanding transmission cycles and their dynamics and consequently human infection. Natural T. cruzi infection is present in captive nonhuman primate colonies in the southern USA. Methods We investigated T. cruzi genetic diversity through a metabarcoding and next-generation sequencing approach of the mini-exon gene to characterize the parasite genotypes circulating in nonhuman primates in southern Louisiana. Results We confirmed the presence of T. cruzi in multiple tissues of 12 seropositive animals, including heart, liver, spleen and gut. The TcI discrete typing unit (DTU) predominated in these hosts, and specifically TcIa, but we also detected two cases of coinfections with TcVI and TcIV parasites, unambiguously confirming the circulation of TcVI in the USA. Multiple mini-exon haplotypes were identified in each host, ranging from 6 to 11. Conclusions The observation of multiple T. cruzi sequence haplotypes in each nonhuman primate indicates possible multiclonal infections. These data suggest the participation of these nonhuman primates in local parasite transmission cycles and highlight the value of these naturally infected animals for the study of human Chagas disease. [ABSTRACT FROM AUTHOR]

Background: In Mexico, estimates of Chagas disease prevalence and burden vary widely. Updating surveillance data is therefore an important priority to ensure that Chagas disease does not remain a barrier to the development of Mexico's most vulnerable populations. Methodology/Principal findings: The aim of this systematic review and meta-analysis was to analyze the literature on epidemiological surveys to estimate Chagas disease prevalence and burden in Mexico, during the period 2006 to 2017. A total of 2,764 articles were screened and 36 were retained for the final analysis. Epidemiological surveys have been performed in most of Mexico, but with variable study scale and geographic coverage. Based on studies reporting confirmed cases (i.e. using at least 2 serological tests), and taking into account the differences of sample sizes, the national estimated seroprevalence of Trypanosoma cruzi infection was 3.38% [95%CI 2.59–4.16], suggesting that there are 4.06 million cases in Mexico. Studies focused on pregnant women, which may transmit the parasite to their newborn during pregnancy, reported an estimated seroprevalence of 2.21% [95%CI 1.46–2.96], suggesting that there are 50,675 births from T. cruzi infected pregnant women per year, and 3,193 cases of congenitally infected newborns per year. Children under 18 years had an estimated seropositivity rate of 1.51% [95%CI 0.77–2.25], which indicate ongoing transmission. Cases of T. cruzi infection in blood donors have also been reported in most states, with a national estimated seroprevalence of 0.55% [95%CI 0.43–0.66]. Conclusions/Significance: Our analysis suggests a disease burden for T. cruzi infection higher than previously recognized, highlighting the urgency of establishing Chagas disease surveillance and control as a key national public health priority in Mexico, to ensure that it does not remain a major barrier to the economic and social development of the country's most vulnerable populations. [ABSTRACT FROM AUTHOR]

The article offers information on the Chagas disease, or American trypanosomiasis, which is caused by the protozoan parasite Trypanosoma cruzi, and has limited treatment options with two drugs available Benznidazole and Nifurtimox. It states that therapeutic vaccination has been proposed for the control of T. cruzi infection. It mentions that preconceptional vaccine aimed at preventing future congenital transmission of the parasite would be good for control of the disease.

Background: The 2020 Sustainable Development goals call for 100% certified interruption or control of the three main forms of Chagas disease transmission in Latin America. However, how much will achieving these goals to varying degrees control Chagas disease; what is the potential impact of missing these goals and if they are achieved, what may be left? Methods: We developed a compartmental simulation model that represents the triatomine, human host, and non-human host populations and vector-borne, congenital, and transfusional T. cruzi transmission between them in the domestic and peridomestic settings to evaluate the impact of limiting transmission in a 2,000 person virtual village in Yucatan, Mexico. Results: Interruption of domestic vectorial transmission had the largest impact on T. cruzi transmission and prevalence in all populations. Most of the gains were achieved within the first few years. Controlling vectorial transmission resulted in a 46.1–83.0% relative reduction in the number of new acute Chagas cases for a 50–100% interruption in domestic vector-host contact. Only controlling congenital transmission led to a 2.4–8.1% (30–100% interruption) relative reduction in the total number of new acute cases and reducing only transfusional transmission led to a 0.1–0.3% (30–100% reduction). Stopping all three forms of transmission resulted in 0.5 total transmission events over five years (compared to 5.0 with no interruption); interrupting all forms by 30% resulted in 3.4 events over five years per 2,000 persons. Conclusions: While reducing domestic vectorial, congenital, and transfusional transmission can successfully reduce transmission to humans (up to 82% in one year), achieving the 2020 goals would still result in 0.5 new acute cases per 2,000 over five years. Even if the goals are missed, major gains can be achieved within the first few years. Interrupting transmission should be combined with other efforts such as a vaccine or improved access to care, especially for the population of already infected individuals. [ABSTRACT FROM AUTHOR]

Background: Chagas disease, caused by the parasite Trypanosoma cruzi, is mainly transmitted by blood-sucking bugs called triatomines. In the Yucatán Peninsula, Mexico, the main vector of T. cruzi is Triatoma dimidiata. While this species may colonize houses in other regions, it is mostly intrusive in Yucatán: it generally lives in sylvan and peridomestic areas, and frequently enters inside homes, likely attracted by potential vertebrate hosts, without establishing colonies. Bugs collected inside homes have a low nutritional status, suggesting that they cannot efficiently feed inside these houses. We hypothesized that this low nutritional status and limited colonization may be associated, at least in part, with the local practice in Mayan communities to sleep in hammocks instead of beds, as this sleeping habit could be an obstacle for triatomines to easily reach human hosts, particularly for nymphal instars which are unable to fly. Methods: We used an experimental chamber in which we placed a miniature bed in one side and a miniature hammock on the other side. After placing a mouse enclosed in a small cage on the bed and another one in the hammock as baits, T. dimidiata bugs were released in the chamber and their activity was video recorded during the night. Results: T. dimidiata adults and nymphs were able to reach the mouse in bed significantly more often than the mouse in hammock (Binomial test, P < 0.0001). Moreover, females reached the mice twice as often as did males. Most of the adult bugs reached the mouse in bed by walking, while they reached the mouse in hammock by flying. Nymphs presented a host-seeking index ten times lower than adult bugs and were also able, on a few occasions (4/132 released bugs), to reach the mouse in hammock. Conclusions: We conclude that sleeping in hammocks, as done in rural Yucatán, makes human hosts less accessible to the bugs. This, combined with other factors (e.g. absence of domestic animals sleeping inside houses), may explain, at least in part, the low nutritional status of bugs collected inside homes and the limited colonization of houses by T. dimidiata in the region. Nevertheless, while this sleeping habit limits contact with the bugs, it does not confer complete protection as adult bugs as well as some nymphs were still able to reach the host in hammock in our study. [ABSTRACT FROM AUTHOR]

OBJECTIVE To describe the current situation of Chagas disease in Ecuador and to evaluate the impact of vector control for the period 2004-2014. METHODS Since 2004, the Ministry of Public Health has formalized activities for the surveillance and control of Chagas disease and we analyzed here available records. RESULTS More than 200 000 houses were surveyed, and 2.6% were found to be infested (95% CI: 2.6-2.7), and more than 51 000 houses were sprayed with residual insecticide, with important yearly variations. A total of 915 cases of T. cruzi infection were registered. The Amazon region is emerging as a high priority area, where nearly half of T. cruzi infection cases originate. The costal region and the southern highland valleys remain important high-risk area. Vector control efforts over the past 10 years have been effective in the coastal region, where T. dimidiata predominates, and resulted in important reductions in house infestation indices in many areas, even reaching negligible levels in some parishes. CONCLUSION Vector efforts need to be sustained and expanded for the elimination of T. dimidiata to be feasible. Novel vector control interventions need to be designed to reduce intrusion by several triatomine species present in the Amazon region and southern Ecuador. Strong political commitment is needed to sustain current achievements and improve the national coverage of these programmes. [ABSTRACT FROM AUTHOR]

Background: Chagas disease is a parasitic disease caused by the protozoan parasite Trypanosoma cruzi. In Mexico, the burden of the disease is difficult to estimate and improving surveillance for Chagas disease is an important priority. We aimed here at determining the seroprevalence of T. cruzi infection in humans in a rural community in Veracruz. Methods: Serum samples (196) were analyzed for T. cruzi infection using five enzyme-linked immunosorbent assay (ELISA) tests: two in-house tests based on crude parasite extract and three commercial ELISA kits. Because of highly discordant results, we further explored the importance of parasite antigens and strains by western-blot analysis. Results: A total of 74 samples (37.7 %) were reactive with at least one ELISA, but discordance among tests was very high. The best agreement was between Chagatest recombinant and Chagatek ELISA (Kappa index = 0.798). The agreement between other combinations of tests ranged from 0.038 to 0.518. Discordant samples were confirmed by western-blot analysis using up to nine parasite strains, giving a seroprevalence of 33.7 %. Conclusions: Commercial tests had a very limited ability to detect T. cruzi infection in the study population. In-house tests based on crude parasite antigens showed a greater sensitivity but were still unable to detect all cases of T. cruzi infection, even when based on a local parasite strain. The high seroprevalence confirmed the hyper-endemicity of T. cruzi infection in the region. Reliable epidemiological surveillance of Chagas disease will require the development of improved diagnostic tests. [ABSTRACT FROM AUTHOR]

Chagas disease has a major impact on human health in Latin America and is becoming of global concern due to international migrations. Trypanosoma cruzi, the etiological agent of the disease, is one of the rare human parasites transmitted by the feces of its vector, as it is unable to reach the salivary gland of the insect. This stercorarian transmission is notoriously poorly understood, despite its crucial role in the ecology and evolution of the pathogen and the disease. The objective of this study was to quantify the probability of T. cruzi vectorial transmission to humans, and to use such an estimate to predict human prevalence from entomological data. We developed several models of T. cruzi transmission to estimate the probability of transmission from vector to host. Using datasets from the literature, we estimated the probability of transmission per contact with an infected triatomine to be 5.8×10−4 (95%CI: [2.6 ; 11.0]×10−4). This estimate was consistent across triatomine species, robust to variations in other parameters, and corresponded to 900–4,000 contacts per case. Our models subsequently allowed predicting human prevalence from vector abundance and infection rate in 7/10 independent datasets covering various triatomine species and epidemiological situations. This low probability of T. cruzi transmission reflected well the complex and unlikely mechanism of transmission via insect feces, and allowed predicting human prevalence from basic entomological data. Although a proof of principle study would now be valuable to validate our models' predictive ability in an even broader range of entomological and ecological settings, our quantitative estimate could allow switching the evaluation of disease risk and vector control program from purely entomological indexes to parasitological measures, as commonly done for other major vector borne diseases. This might lead to different quantitative perspectives as these indexes are well known not to be proportional one to another. Author Summary: Chagas disease is a parasitic disease affecting about 10 million people, often living in poor conditions, and the disease contributes to impede their development. As several other infectious diseases (malaria, dengue or sleeping sickness), it is transmitted by blood-feeding insect vectors. While most other human pathogens are directly injected with the vector's saliva, Chagas disease parasite is transmitted through the insect's feces that are deposited on the skin during bloodmeals, which seems to be a very inefficient process. The probability of such transmission to human has thus been very hard to estimate, although it is crucial to predict where people are at risk and design effective control strategies. Using mathematical models integrating data on vectors and humans collected across Latin America, we estimated that for several vector species transmission occurs in 1 over 900–4000 contacts with infected insects. We further showed that our estimate allows prediction of human infection rates in various ecological conditions. These models will provide health policy makers with improved indexes to better prioritize/evaluate of the outcomes of vector control programs. [ABSTRACT FROM AUTHOR]

Chagas disease, caused by the parasite Trypanosoma cruzi, is a neglected tropical disease that is prevalent in Latin America and is a leading cause of heart disease in the region. However, the disease is also present in North America, with Mexico and the United States having a significant number of cases. Poverty and lack of access to healthcare contribute to the transmission of the disease. There is a lack of awareness and surveillance of Chagas disease in North America, and efforts are needed to improve diagnosis, treatment, and research for the disease. [Extracted from the article]

Chagas' disease is an important health problem in most Latin American countries, and a concern in dog populations, which act as a reservoir. We showed in previous studies that a therapeutic DNA vaccine could partially control the pathology after Trypanosoma cruzi infection in mice, and this vaccine may represent an alternative treatment for Chagas' disease. Here we evaluated the therapeutic efficacy of this vaccine in experimentally infected dogs for up to 2 months after infection. Our results suggest that DNA vaccine treatment may affect the immune response and delay Chagas' disease progression in T. cruzi–infected dogs, and confirm the potential of this novel treatment. [ABSTRACT FROM AUTHOR]

Objectives Mothers with Chagas’ disease can transmit Trypanosoma cruzi to their fetuses, who often become carriers of the infection and are then at risk of developing severe cardiac disease later in the course of their lives. If identified early enough after birth, the infected newborns can be treated and cured. Our objective was to review the data available in Canada, Mexico, and the United States and to discuss the need for prevention programs. Methods We reviewed the literature and estimated the number of seropositive mothers and newborns infected by T. cruzi. Results We estimate that about 40,000 pregnant women and 2,000 newborns are likely to be infected by T. cruzi in North America. We have not identified any ongoing prevention programs. Conclusions Mother-to-child transmission of T. cruzi has all the characteristics required to be a public health priority, as it is relatively frequent, severe, identifiable, and treatable. In reality, it is a neglected disease and a missed opportunity. It is urgent to better understand the epidemiology of mother-to-child transmission of T. cruzi in North America and to develop effective prevention programs. [ABSTRACT FROM AUTHOR]

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is a major public health problem in most of Latin America. A key priority is the development of new treatments, due to the poor efficacy of current ones. We report here the comparative evaluation of therapeutic DNA vaccines encoding various T. cruzi antigens. ICR mice infected with 500 parasites intraperitoneally were treated at 5 and 12 days postinfection with 20 μg of plasmid DNA encoding T. cruzi antigens TSA-1, TS, ASP-2-like, Tc52 or Tc24. Treatment with plasmid encoding TS and/or ASP-2-like antigens had no significant effect on parasitemia or survival. Treatment with Tc52 DNA significantly reduced parasitemia, as well as cardiac parasite burden, and improved survival, although myocarditis was not significantly affected. Finally, treatment with plasmids encoding Tc24 and TSA-1 induced the most complete control of disease as evidenced by significant reductions in parasitemia, mortality, myocarditis and heart parasite burden. These data demonstrate that therapeutic vaccine efficacy is dependent on the antigen and suggest that DNA vaccines encoding Tc24, TSA-1, and Tc52 represent the best candidates for further studies of a therapeutic vaccine against Chagas disease. [ABSTRACT FROM AUTHOR]

Chagas disease is an important vector-borne neglected tropical disease that causes great health and economic losses. The etiological agent, Trypanosoma cruzi, is a protozoan parasite endemic to the Americas, comprised by important diversity, which has been suggested to contribute to poor serological diagnostic performance. Current nomenclature describes seven discrete typing units (DTUs), or lineages. We performed the first large scale analysis of T. cruzi diversity among 52 previously published genomes from strains covering multiple countries and parasite DTUs and assessed how different markers summarize this genetic diversity. We also examined how seven antigens currently used in commercial serologic tests are conserved across this diversity of strains. DTU structuration was confirmed at the whole-genome level, with evidence of sub-DTU diversity, associated in part to geographic structuring. We observed very comparable phylogenetic tree topographies for most of the 32 markers investigated, with clear clustering of sequences by DTU, and a few of these markers suggested some degree of intra-lineage diversity. At least three of the currently used antigens represent poorly conserved sequences, with sequences used in tests quite divergent from sequences in many strains. Most markers are well suited for estimating parasite diversity to DTU level, and a few are particularly well-suited to assess intra-DTU diversity. Analysis of antigen sequences across all strains indicates that antigenic diversity is a likely explanation for limited diagnostic performance in Central and North America. [ABSTRACT FROM AUTHOR]

A consequence of the late awareness of Chagas disease in North America is that many early studies were never published in peer-reviewed journals and are not easily accessible for inclusion in systematic reviews. We reviewed data from the state of Guanajuato, Mexico, as an illustration. Three population-based surveys have been performed between 1991 and 2002 and were never fully published. Systematic reviews should recognize this publication bias. [ABSTRACT FROM AUTHOR]

Background: In the Yucatán Peninsula, Mexico, Triatoma dimidiata is the main vector of Trypanosoma cruzi, the causative agent of Chagas disease. Little effort has been made to identify blood meal sources of T. dimidiata in natural conditions in this region, although this provides key information to disentangle T. cruzi transmission cycles and dynamics and guide the development of more effective control strategies. We identified the blood meals of a large sample of T. dimidiata bugs collected in different ecotopes simultaneously with the assessment of bug infection with T. cruzi, to disentangle the dynamics of T. cruzi transmission in the region. Methods: A sample of 248 T. dimidiata bugs collected in three rural villages and in the sylvatic habitat surrounding these villages was used. DNA from each bug midgut was extracted and bug infection with T. cruzi was assessed by PCR. For blood meal identification, we used a molecular assay based on cloning and sequencing following PCR amplification with vertebrate universal primers, and allowing the detection of multiple blood meals in a single bug. Results: Overall, 28.7% of the bugs were infected with T. cruzi, with no statistical difference between bugs from the villages or from sylvatic ecotopes. Sixteen vertebrate species including domestic, synanthropic and sylvatic animals, were identified as blood meal sources for T. dimidiata. Human, dog and cow were the three main species identified, in bugs collected in the villages as well as in sylvatic ecotopes. Importantly, dog was highlighted as the main blood meal source after human. Dog was also the most frequently identified animal together with human within single bugs, and tended to be associated with the infection of the bugs. Conclusions: Dog, human and cow were identified as the main mammals involved in the connection of sylvatic and domestic transmission cycles in the Yucatán Peninsula, Mexico. Dog appeared as the most important animal in the transmission pathway of T. cruzi to humans, but other domestic and synanthropic animals, which most were previously reported as important hosts of T. cruzi in the region, were evidenced and should be taken into account as part of integrated control strategies aimed at disrupting parasite transmission. [ABSTRACT FROM AUTHOR]

Trypanosoma cruzi is a protozoan parasite causing Chagas disease, with a complex life cycle involving different stages in insect vectors and mammalian hosts. Amastigotes are an intracellular form that replicates in the cytoplasm of host cells, and recent studies suggested that dormant forms may be contributing to parasite persistence, suggesting cellular heterogeneity among amastigotes. We investigated here if a transcriptomic approach could identify some heterogeneity in intracellular amastigotes and identify a dormant population. We used gene expression data derived from bulk RNA-sequencing of T. cruzi infection of human fibroblasts for deconvolution using CDSeq, which allows to simultaneously estimate amastigote cell-type proportions and cell-type-specific expression profiles. Six amastigote subpopulations were identified, confirming intracellular amastigotes heterogeneity, and one population presented characteristics of non-replicative dormant parasites, based on replication markers and TcRAD51 expression. Transcriptomic approaches appear to be powerful to understand T. cruzi cell differentiation and expansion of these studies could provide further insight on the role different cell types in parasite persistence and Chagas disease pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Triatoma dimidiata is one of the main vectors of Chagas disease, and it has been shown to be a species complex. In the Yucatán peninsula, Mexico, vector populations are non-domiciliated, and the transmission of Trypanosoma cruzi thus critically relies on vector dispersal. This leads us to study the morphologic variations in T. dimidiata wings with respect to genetic factors (sex and genotype at the ITS-2 locus), geographic location, and T. cruzi-infection status. Females were found to have larger and more symmetrical wings than males. Wing shape was influenced by ITS-2 genotypes, although differences are unlikely sufficient to allow taxonomic discrimination of the sibling species. Hybrids were shown to have similar fluctuating asymmetries in wing size and shape as parental species, but the level of asymmetry in shape varied slightly between villages. The two later findings are consistent with a high level of gene flow between parental species, and the high dispersal potential of these non-domiciliated vectors. More surprisingly, individuals infected with T. cruzi were found to have larger wings than non-infected ones. This effect, which was consistently observed across sexes, genotypes and villages, is likely to be due to a direct impact of T. cruzi on insect development. Sex and infection status are thus likely to be key factors influencing vector dispersal with important impacts on disease transmission, since dispersal directly controls the domestic abundance of these vectors. These aspects should be investigated further to fully capture the ecology and evolution of Chagas disease transmission by non-domiciliated vectors. [Copyright &y& Elsevier]

• Triatoma dimidiata in Belize fed on at least 13 vertebrate species including humans. • Trypanosoma cruzi TcI and TcIV parasite discrete typing units were detected. • Parasite sequences from Belize differed from sequences from North and South America. • T. dimidiata harbored a diverse bacterial microbiota with ontogenic changes. In Belize, the main vector for Trypanosoma cruzi , the agent of Chagas disease, is Triatoma dimidiata , but transmission cycles and the risk for human infection are unclear. Therefore, the aim of this study was to identify T. dimidiata blood feeding sources and its parasite and microbial diversity, in order to reconstruct T. cruzi parasite transmission ecology in southern Belize. A metabarcoding approach based on deep sequencing of markers was used for bug taxonomy, blood meal sources, T. cruzi genotypes, and microbiota composition. Bugs were collected in 13 villages of Toledo district. Bugs fed on at least 13 species, from domestic hosts such as humans, dogs, cows, and pigs, to synanthropic species such as mice, rats, and opossums, and sylvatic species such as deer, peccary, and kinkajou, in agreement with an opportunistic feeding behavior. Nonetheless, most feeding focused on a few species, including humans. Infection with T. cruzi was detected in 24 of 39 bugs (62%), and the analysis of 242 T. cruzi mini-exon sequences (average 10 ± 5 haplotypes per bug) indicated the presence of TcI and TcIV parasite discrete typing units (DTUs). However, for both DTUs, sequences from Belize mostly clustered apart from sequences from North and South America, suggesting the local differentiation of parasites. T. dimidiata also harbored a diverse bacterial microbiota, with ontogenic changes suggesting microbiota maturation during nymphal development. Together, these results indicate a significant risk for T. cruzi infection in humans. They also highlight the need to better characterize the diversity of T. cruzi strains in the region and its impact on disease epidemiology. [ABSTRACT FROM AUTHOR]

Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi . In Ecuador, Triatoma dimidiata and Rhodnius ecuadoriensis are the main vector species, responsible for over half of the cases of T. cruzi infection in the country. T. dimidiata is believed to have been introduced in Ecuador during colonial times, and its elimination from the country is thus believed to be feasible. We investigated here the molecular ecology of T. dimidiata and T. cruzi in costal Ecuador to further guide control efforts. Analysis of the Internal Transcribed Spacer 2 (ITS-2) of 23 specimens from Progreso, Guayas, unambiguously supported the likely importation of T. dimidiata from Central America to Ecuador. The observation of a very high parasite infection rate (54%) and frequent feeding on humans (3/5) confirmed a continued risk of transmission to humans. All genotyped parasites corresponded to TcI DTU and Trypanosoma rangeli was not detected in T. dimidiata . TcI subgroups corresponded to TcIa (25%), and mixed infections with TcIa and TcId (75%). Further studies should help clarify T. cruzi genetic structure in the country, and the possible impact of the introduction of T. dimidiata on the circulating parasite strains. The elevated risk posed by this species warrants continuing efforts for its control, but its apparent mobility between peridomestic and domestic habitats may favor reinfestation following insecticide spraying. [ABSTRACT FROM AUTHOR]

Abstract: Chagas disease is a major public health problem, with about 10 million infected people, and DNA vaccines are a promising alternative for the control of Trypanosoma cruzi, the causing agent of the disease. We tested here a new DNA vaccine encoding a combination of two leading parasite antigens, TSA-1 and Tc24, for the prevention and therapy of T. cruzi infection. Immunized Balb/c mice challenged by T. cruzi presented a significantly lower parasitemia and inflammatory cell density in the heart compared to control mice. Similarly, the therapeutic administration of the DNA vaccine was able to significantly reduce the parasitemia and inflammatory reaction in acutely infected Balb/c and C57BL/6 mice, and reduced cardiac tissue inflammation in chronically infected ICR mice. Therapeutic vaccination induced a marked increase in parasite-specific IFNγ producing CD4+ and CD8+ T cells in the spleen as well as an increase in CD4+ and CD8+ T cells in the infected cardiac tissue. In addition, some effect of the DNA vaccine could still be observed in CD4-knockout C57BL/6 mice, which presented a lower parasitemia and inflammatory cell density, but not in CD8-deficient mice, in which the vaccine had no effect. These results indicate that the activation of CD8+ T cells plays a major role in the control of the infection by the therapeutic DNA vaccine, and to a somewhat lesser extent CD4+ T cells. This observation opens interesting perspectives for the potentiation of this DNA vaccine candidate by including additional CD8+ T cell antigens/epitopes in future vaccine formulations. [Copyright &y& Elsevier]

Abstract: Chagas disease (or American trypanosomiasis) is a parasitic disease of major public health importance, caused by Trypanosoma cruzi, which presents extensive genetic diversity. The parasite has been classified into six lineages or discrete typing units (TcI to TcVI) and we performed here the molecular characterization of the strains present in Triatoma dimidiata, the main vector in central Veracruz, Mexico. Unexpectedly, TcI only represented 9/33 strains identified (27%), and we reported for the first time the presence of TcII, TcIII, TcIV and TcV strains in Mexico, at a relatively high frequency (13–27% each). Our observations indicate a much greater diversity of T. cruzi DTUs than previously estimated in at least part of Mexico. These results have important implications for the understanding of the phylogeography of T. cruzi DTUs and the epidemiology of Chagas disease in North America. [Copyright &y& Elsevier]