Comparative epidemiology of genetic lineages of Trypanosoma cruzi.
Keywords: Trypanosomatidae; Trypanosoma cruzi; Chagas disease; Molecular epidemiology; Diagnosis; Pathogenesis; Disease control; Genomics; Population genetics; Phylogenetics.
The focus of this multidisciplinary proposal is to elucidate the epidemiology of the genetic lineages of T. cruzi, for improved understanding and prevention of Chagas disease. The project will unite skills in genotyping, genomics, genetics and pathogenesis in Europe with considerable compatible skills in South America, and with key research in endemic areas that have distinct characteristics. The proposal is intended to be high impact in terms of both research progress and fostering of collaborative networks. Aim: Elucidate the epidemiology of the genetic lineages of T. cruzi, for improved understanding and prevention of Chagas disease. Technology development: 1. Develop further and apply MLST; PCR-RFLP and MLMT to the analysis of genetic populations of T. cruzi, 2. Sequence the unresolved genome of T. cruzi I, 3. Develop lineage specific diagnosis, 4. Develop an oligochromatography PCR-dipstick procedure for detection of T. cruzi. Molecular epidemiology: 5. Pilot studies of association between genetic lineage, clinical outcome, and prevalence of congenital infection, 6. Map the silvatic vector, silvatic mammal, human and ecological associations of the T. cruzi genotypes IId,e,b,a. 7. Compare lineage specific pathogenesis and transmissibility of congenital infection in a mouse model, and compare lineage susceptibility to drugs in vitro. Population genetics and phylogenetics: 8. Re-evaluate the population genetics and evolution of T. cruzi lineages. International cryobank and database: 9. Establish in South America an accessible, expanded, international cryobank for T. cruzi, 10. Establish a website and database for outputs of the project.
The project encompasses the desirable characteristics prescribed by the call, in that they include: genomics/proteomics; effective, innovative relevance to disease, pathogenesis, drugs, interventions; an integrated multidisciplinarity, and capacity building, networking and training in endemic regions.
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Trypanosoma cruzi, the agent of Chagas disease, is known to be a heterogeneous complex of organisms, predominantly clonal but with a proven capacity for genetic hybridisation. Genetic lineages have been defined, named T. cruzi I, II (a, b, c, d, e), however, understanding of their comparative biology and public health importance is fragmentary, and there are practical difficulties in simply discerning the lineages and the relationships between them. The focus of this multidisciplinary proposal is therefore to elucidate the epidemiology of the genetic lineages of T. cruzi, for improved understanding and prevention of Chagas disease. The proposal is designed to take an integrated approach to the following questions:
What is the most practical, high-resolution method of lineage identification that can be deployed in the field? How can multiclonal infections be detected and analysed? How does the quite distinct genome of T. cruzi I compare with that of T. cruzi II?
How can the fundamental question of the link between T. cruzi genotypes and the clinical outcome of Chagas disease be investigated? What are the silvatic hosts of the main agents of human disease, namely: T. cruzi IId and IIe in Bolivia and the Chaco; IIb in Brazil, and IIa, secondary agent in Venezuela? How do the genotypes influence the biologies, transmissibilities, pathogenesis and drug susceptibilities of the lineages?
How will understanding of the lineages change with more extensive sampling and improved phylogenetic analysis using combined molecular datasets?
Elucidate the epidemiology of the genetic lineages of T. cruzi, for improved understanding and prevention of Chagas disease.
This project will profoundly improve knowledge and understanding of the epidemiology of the most significant parasitic disease in the Americas, bringing together research groups in Europe and South America with shared interests, such that they work together in harmony on common objectives. Outputs of the project will facilitate understanding the diversity of clinical manifestations and the reduction of the burden of disease, in summary:
Overall, this will bring technology and collaborative research on the molecular epidemiology of T. cruzi to a new synthesis of understanding, with substantial enhancement of interaction between European and South American scientists.
Please refer to expected results, above, in addition:
By application of molecular tools for identification of T. cruzi lineages and local use of the methods, wider and sustained molecular epidemiological studies will be enabled in the endemic regions, and comparative studies between endemic regions.
The molecular methods that will be developed in this project will also provide an important means of molecular tracking of the origin of T. cruzi isolates, thus whether a European infection was imported from Central America or South America or locally acquired from transfusion of contaminated blood.
The project will contribute towards improved measures for reducing the future burden of Chagas disease. Insight on drug susceptibilities and comparative pathogenesis of the genetic lineages will be relevant to improvement of treatment and management of cases. Identifying the role of mammal reservoir hosts and vectors will define which are fundamentally relevant to disease transmission and are concerns for future interventions, and will guide the further development of control strategies. The expanded international repository of representative isolates of T. cruzi will greatly facilitate future research.