A Genomic Approach to Toxoplasma gondii Pathogenicity in South American Immunocompetent Populations – ToxoPath

Toxoplasma gondii (Tg) is a zoonotic protozoan parasite with global distribution, infecting around 30% of the human population and causing toxoplasmosis. Its definitive hosts are domestic cats (domestic cycle) and wild felids (sylvatic cycle), while all warm-blooded species, including humans, serve as intermediate hosts.
Historically, infection with Tg has been long considered essentially asymptomatic or mild, except for certain risk groups, such as the developing fetus in the case of congenital infection (CT), and immunodepressed (ID) patients. However, in South America, the impact of toxoplasmosis is particularly high. A high prevalence of severe acquired forms of ocular toxoplasmosis (OT) in immunocompetent patients (IC) has been reported in several regions. Additionally, multiple cases of life-threatening disseminated toxoplasmosis (DT), occasionally accompanied by ocular involvement (DT+OT), have been documented in IC in French Guiana, Brazil and Colombia. The clinical and epidemiological specificities of South American toxoplasmosis are intriguing, as they clearly contrast with those observed in other parts of the world.
It has been hypothesized that Tg strains involved in severe toxoplasmosis in IC individuals display specific virulence traits associated with augmented pathogenicity in humans. In French Guiana, the strains responsible for DT (or DT+OT) in IC patients belong to the so-called Amazonian wild population of Tg, which is genetically well-characterized. However, Tg strains causing OT in Colombia, Brazil, and Argentina remain poorly characterized at the genomic level. This knowledge gap leaves unresolved whether DT and OT represent a clinical continuum driven by genetically related Tg strains or if distinct strains are responsible for each manifestation. From a mechanistical perspective, the specific virulence traits that underly this augmented pathogenicity in humans are barely known. Extensive research identified Tg virulence genes in mice involving interactions between parasite-secreted proteins and host immunity-related GTPases (IRG), an immune pathway absent in humans.
A recent study revealed that modern domestic South American Tg populations emerged from massive hybridizations between domestic Old-World lineages introduced to South America by European settlers, and native wild South American strains, including the highly human-pathogenic Amazonian Tg strains. The hypothesis of the present proposal is that certain hybrid strains inherited pathogenic traits from wild South American strains, potentially explaining the region's disproportionate burden associated with toxoplasmosis.
This project seeks to unravel the mechanisms underlying the unique clinical severity of human toxoplasmosis in South America in light of recent advances in Tg genomics. By employing advanced genomic methods, we will test whether hybrid strains, combining ancestral virulence factors with domestic adaptations, are responsible of the severe toxoplasmosis burden in immunocompetent South American populations. Additionally, a comparison between whole-genomes of Tg strains associated with severe pathogenicity in IC patients and those causing mild symptoms or observed in ID and CT cases will be carried out to identify Tg virulence genes involved in human pathogenesis, offering critical insights into the molecular mechanisms employed by Tg to infect the human host.