About
Gerald Spaeth, PI
Pascale Pescher, co-PI
Mariana Boité (Fiocruz Rio de Janeiro, Brazil), coordinator
American Visceral Leishmaniasis (AVL) is a persistent public health challenge in the Americas, representing one of the main failures of infectious disease management in Brazil. Changes in demographic traits of the disease and the recent description of poor response to miltefosine treatment associated with a natural resistance of strains, enhances the concerns. Even though VL represents a major national health problem, only little attention is given to the main important player – the New World (NW) parasite itself. The recently published paper and review authored by us addressed this important shortcoming by revealing parasite diversity and its genome plasticity as key factors in AVL epidemiology. We have discussed that, although being of the same origin, Old World and NW L. infantum strains were exposed to distinct environmental conditions in the last 500 years, since the parasites’ introduction in the NW by the Hispanic conquest, leading to different evolutionary trajectories for both groups of parasites. We described a major evolutive transformation among the imported L. infantum to the continent: the widespread distribution of an inherited genomic trait, a full 12Kb genomic deletion that likely results from long-term adaptation to the NW ecology. Coupled with these transformations likely coexists biological features that ultimately affect relevant epidemiological traits, such as drug resistance, virulence and transmissibility by the vectors. The EvoLeish proposal will evaluate such traits, specifically differences in virulence and host immune response between NW L. infantum genotypes, and their association with the deletion. By doing so, the EvoLeish will bring immediate benefits to the surveillance of AVL. Importantly, this ecological scenario and the naturally mutated field parasites provide an unprecedented opportunity to uncover novel mechanisms of Leishmania environmental adaptation and fitness gain under clinically relevant conditions.
Our recently published results revealed the widespread distribution and high frequency of deletion- carrying (DEL) L. infantum strains (126 of 177) and the occurrence of a divergent non-deletion (NonDEL) group in southwestern Brazil. Importantly, until now, this deletion has been detected only among NW strains and represent an ancestral, inherited trait, suggesting that this important genomic change is under positive selection in Brazil and thus likely highly relevant to the local dynamics of L. infantum infection. Significantly, the deletion spans across the four copies of tetrasomic chromosome 31 (chr31), the only stable chromosomal amplification within the mosaic aneuploidy of Leishmania parasites. The deletion of all four alleles further supports strong, environmental selection, suggesting that the deletion provides a fitness advantage for L. infantum in Brazil. Analyzing the mechanisms underlying this fitness gain is the final goal of our proposal. The essential nature of the deletion in parasite viability and infectivity raises one of the key questions addressed in our proposal on the compensatory mechanisms evolved in Brazilian L. infantum strains that allow for their deletion to occur. The biological effect of this deletion and the presence of compensatory responses at genomic, post-transcriptional and translational levels will be assessed in our proposal. The multi-disciplinary EvoLeish project is based on the above commented epidemiological data, which motivate the following objectives: i) the phenotypic characterization of Brazilian L. infantum isolates carrying the sub- chromosomal deletion (Del) or not (NonDEL) by in vivo and in vitro infection models to asses immune response and virulence profiles, ii) the functional-genetic and systems-level analysis of their genomic and no-genomic adaptation, and iii) the immunomodulatory consequences of this adaptation. Through a series of complementary tasks, these objectives synergize the expertise of the partner teams in order to reveal how the genomic deletion specific to NW L. infantum is compensated and influences host/parasite interaction to promote Leishmania fitness.