Pharmacokinetic-pharmacodynamic modeling of benznidazole and its antitrypanosomal activity in a murine model of chronic Chagas disease.

Background: There is an urgent need for improved treatments for Chagas disease, a neglected tropical infection caused by the protozoan parasite Trypanosoma cruzi. Benznidazole, the first line therapy, has severe limitations such as poor tolerability and variable efficacy in the chronic stage of infection. To optimize dosing regimens, a better understanding of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for benznidazole is crucial.

Intermittent suppressive posaconazole therapy is ineffective at mitigating cardiac and digestive tract pathologies in an experimental model of chronic Chagas disease.

Infections with cause Chagas disease, a chronic condition that can give rise to debilitating cardiac and/or gastrointestinal damage. However, it is unclear why only ~30% of individuals progress to symptomatic pathology, why this can take decades to become apparent, and why there is such a wide range of disease outcomes. Disease pathology is a long-term cumulative process resulting from collateral damage caused by inflammatory immune responses that continually eliminate transient parasite infections in the heart and/or gastrointestinal tract.

Animal models for exploring Chagas disease pathogenesis and supporting drug discovery.

Infections with the parasitic protozoan cause Chagas disease, which results in serious cardiac and/or digestive pathology in 30%-40% of individuals. However, symptomatic disease can take decades to become apparent, and there is a broad spectrum of possible outcomes. The complex and long-term nature of this infection places a major constraint on the scope for experimental studies in humans.

Dynamics of Trypanosoma cruzi infection in hamsters and novel association with progressive motor dysfunction.

Chagas disease is a zoonosis caused by the protozoan parasite Trypanosoma cruzi. Clinical outcomes range from long-term asymptomatic carriage to cardiac, digestive, neurological and composite presentations that can be fatal in both acute and chronic stages of the disease. Studies of T.

A panel of phenotypically and genotypically diverse bioluminescent:fluorescent Trypanosoma cruzi strains as a resource for Chagas disease research.

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that displays considerable genetic diversity. Infections result in a range of pathological outcomes, and different strains can exhibit a wide spectrum of anti-parasitic drug tolerance. The genetic determinants of infectivity, virulence and therapeutic susceptibility remain largely unknown.

Cardiac Abnormalities in a Predictive Mouse Model of Chagas Disease.

Chronic Chagas cardiomyopathy (CCC) results from infection with the protozoan parasite and is a prevalent cause of heart disease in endemic countries. We previously found that cardiac fibrosis can vary widely in C3H/HeN mice chronically infected with JR strain, mirroring the spectrum of heart disease in humans. In this study, we examined functional cardiac abnormalities in this host:parasite combination to determine its potential as an experimental model for CCC.

Impact of Visceral Leishmaniasis on Local Organ Metabolism in Hamsters.

is an intracellular parasite with different species pathogenic to humans and causing the disease leishmaniasis. causes visceral leishmaniasis (VL) that manifests as hepatosplenomegaly, fever, pancytopenia and hypergammaglobulinemia. If left without treatment, VL can cause death, especially in immunocompromised people.

Microevolution of reveals hybridization and clonal mechanisms driving rapid genome diversification.

Protozoa and fungi are known to have extraordinarily diverse mechanisms of genetic exchange. However, the presence and epidemiological relevance of genetic exchange in , the agent of Chagas disease, has been controversial and debated for many years. Field studies have identified both predominantly clonal and sexually recombining natural populations.

Incomplete Recruitment of Protective T Cells Is Associated with Trypanosoma cruzi Persistence in the Mouse Colon.

Trypanosoma cruzi is the etiological agent of Chagas disease. Following T cell-mediated suppression of acute-phase infection, this intracellular eukaryotic pathogen persists long-term in a limited subset of tissues at extremely low levels. The reasons for this tissue-specific chronicity are not understood.

Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale.

Digestive Chagas disease (DCD) is an enteric neuropathy caused by Trypanosoma cruzi infection. The mechanism of pathogenesis is poorly understood and the lack of a robust, predictive animal model has held back research. We screened a series of mouse models using gastrointestinal tracer assays and in vivo infection imaging systems to discover a subset exhibiting chronic digestive transit dysfunction and significant retention of faeces in both sated and fasted conditions.

Repeat-Driven Generation of Antigenic Diversity in a Major Human Pathogen, .

, a zoonotic kinetoplastid protozoan parasite, is the causative agent of American trypanosomiasis (Chagas disease). Having a very plastic, repetitive and complex genome, the parasite displays a highly diverse repertoire of surface molecules, with pivotal roles in cell invasion, immune evasion and pathogenesis. Before 2016, the complexity of the genomic regions containing these genes impaired the assembly of a genome at chromosomal level, making it impossible to study the structure and function of the several thousand repetitive genes encoding the surface molecules of the parasite.

Culture-free genome-wide locus sequence typing (GLST) provides new perspectives on Trypanosoma cruzi dispersal and infection complexity.

Analysis of genetic polymorphism is a powerful tool for epidemiological surveillance and research. Powerful inference from pathogen genetic variation, however, is often restrained by limited access to representative target DNA, especially in the study of obligate parasitic species for which ex vivo culture is resource-intensive or bias-prone. Modern sequence capture methods enable pathogen genetic variation to be analyzed directly from host/vector material but are often too complex and expensive for resource-poor settings where infectious diseases prevail.

Bioluminescent:Fluorescent Trypanosoma cruzi Reporter Strains as Tools for Exploring Chagas Disease Pathogenesis and Drug Activity.

Chagas disease results from infection with the trypanosomatid parasite Trypanosoma cruzi. Progress in developing new drugs has been hampered by the long term and complex nature of the condition and by our limited understanding of parasite biology. Technical difficulties in assessing the parasite burden during the chronic stage of infection have also proven to be a particular challenge.

Opportunities, Pitfalls, and Alternatives in Adapting Electronic Health Records for Health Services Research.

Electronic health records (EHRs) offer the potential to study large numbers of patients but are designed for clinical practice, not research. Despite the increasing availability of EHR data, their use in research comes with its own set of challenges. In this article, we describe some important considerations and potential solutions for commonly encountered problems when working with large-scale, EHR-derived data for health services and community-relevant health research.

Host-parasite dynamics in Chagas disease from systemic to hyper-local scales.

Trypanosoma cruzi is a remarkably versatile parasite. It can parasitize almost any nucleated cell type and naturally infects hundreds of mammal species across much of the Americas. In humans, it is the cause of Chagas disease, a set of mainly chronic conditions predominantly affecting the heart and gastrointestinal tract, which can progress to become life threatening.

Analysis of Trypanosoma cruzi Persistence Foci at Single-Cell Resolution.

Infections with are usually lifelong despite generating a strong adaptive immune response. Identifying the sites of parasite persistence is therefore crucial to understanding how avoids immune-mediated destruction. However, this is a major technical challenge, because the parasite burden during chronic infections is extremely low.

Drug-cured experimental Trypanosoma cruzi infections confer long-lasting and cross-strain protection.

Background: The long term and complex nature of Chagas disease in humans has restricted studies on vaccine feasibility. Animal models also have limitations due to technical difficulties in monitoring the extremely low parasite burden that is characteristic of chronic stage infections. Advances in imaging technology offer alternative approaches that circumvent these problems.

Fatal progression of experimental visceral leishmaniasis is associated with intestinal parasitism and secondary infection by commensal bacteria, and is delayed by antibiotic prophylaxis.

Leishmania donovani causes visceral leishmaniasis (VL), which is typically fatal without treatment. There is substantial variation between individuals in rates of disease progression, response to treatment and incidence of post-treatment sequelae, specifically post-kala-azar dermal leishmaniasis (PKDL). Nevertheless, the majority of infected people are asymptomatic carriers.

Intracellular DNA replication and differentiation of Trypanosoma cruzi is asynchronous within individual host cells in vivo at all stages of infection.

Investigations into intracellular replication and differentiation of Trypanosoma cruzi within the mammalian host have been restricted by limitations in our ability to detect parasitized cells throughout the course of infection. We have overcome this problem by generating genetically modified parasites that express a bioluminescent/fluorescent fusion protein. By combining in vivo imaging and confocal microscopy, this has enabled us to routinely visualise murine infections at the level of individual host cells.

Exploiting Genetically Modified Dual-Reporter Strains to Monitor Experimental Trypanosoma cruzi Infections and Host-Parasite Interactions.

Trypanosoma cruzi is the causative agent of Chagas disease, the most important parasitic infection in Latin America. Despite a global research effort, there have been no significant treatment advances for at least 40 years. Gaps in our knowledge of T.

Assessing the Effectiveness of Curative Benznidazole Treatment in Preventing Chronic Cardiac Pathology in Experimental Models of Chagas Disease.

Chagasic heart disease develops in 30% of those infected with the protozoan parasite , but can take decades to become symptomatic. Because of this, it has been difficult to assess the extent to which antiparasitic therapy can prevent the development of pathology. We sought to address this question using experimental murine models, exploiting highly sensitive bioluminescent imaging to monitor curative efficacy.

Imaging the development of chronic Chagas disease after oral transmission.

Chagas disease is a zoonosis caused by the protozoan parasite Trypanosoma cruzi. Transmission cycles are maintained by haematophagous triatomine bug vectors that carry infective T. cruzi in their faeces.