Genome-Scale Multilocus Microsatellite Typing of Trypanosoma cruzi Discrete Typing Unit I Reveals Phylogeographic Structure and Specific Genotypes Linked to Human Infection

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Abstract
Trypanosoma cruzi is the most important parasitic infection in Latin America and is also genetically highly diverse, with at least six discrete typing units (DTUs) reported: Tc I, IIa, IIb, IIc, IId, and IIe. However, the current six-genotype classification is likely to be a poor reflection of the total genetic diversity present in this undeniably ancient parasite. To determine whether epidemiologically important information is “hidden” at the sub-DTU level, we developed a 48-marker panel of polymorphic microsatellite loci to investigate population structure among 135 samples from across the geographic distribution of TcI. This DTU is the major cause of resurgent human disease in northern South America but also occurs in silvatic triatomine vectors and mammalian reservoir hosts throughout the continent. Based on a total dataset of 12,329 alleles, we demonstrate that silvatic TcI populations are extraordinarily genetically diverse, show spatial structuring on a continental scale, and have undergone recent biogeographic expansion into the southern United States of America. Conversely, the majority of human strains sampled are restricted to two distinct groups characterised by a considerable reduction in genetic diversity with respect to isolates from silvatic sources. In Venezuela, most human isolates showed little identity with known local silvatic strains, despite frequent invasion of the domestic setting by infected adult vectors. Multilocus linkage indices indicate predominantly clonal parasite propagation among all populations. However, excess homozygosity among silvatic strains and raised heterozygosity among domestic populations suggest that some level of genetic recombination cannot be ruled out. The epidemiological significance of these findings is discussed. The arrival of the Trypanosoma cruzi online genome now provides vital information for the study of Chagas disease. Using this resource, we identified and developed a genome-scale panel of rapidly evolving microsatellite markers that can be used to unravel the micro-epidemiology of this parasite. We then tested these against a panel of isolates belonging to the most widely occurring and ancient major lineage, T. cruzi I (TcI). Our study includes samples from across the geographical distribution of this lineage, including isolates from wild vectors, domestic vectors, as well as wild mammalian reservoirs and human hosts. This is the first time T. cruzi has been subjected to such high-resolution population genetic analysis. Our study shows that important epidemiological information lies at the intra-lineage level, especially when wild and domestic populations of parasite are compared. Crucially, in Venezuela, where Chagas disease may be resurgent despite decades of control effort, genotypes of parasites found in the wild are rarely represented in humans, despite evidence that infected wild vectors do invade houses. In this manuscript, we examine the epidemiological implications of this finding and others, and suggest how the approach we have developed can now be used to investigate the true nature of parasite transmission at Chagas disease foci throughout the Americas.