Toxoplasma gondii genotyping in 2,467 human toxoplasmosis cases from France and other geographical origins: genetic diversity and clinical associations

Background Toxoplasma gondii exhibits marked variation in genetic diversity, yet the relationships between parasite genotype and clinical presentation in humans remain poorly understood. We investigated the diversity of T. gondii strains infecting humans and their associations with different forms of toxoplasmosis. Methodology/Principal Findings We retrospectively analyzed 2,467 T. gondii-positive human clinical cases collected in France through a nationwide network of hospital parasitology diagnostic units over more than four decades. Cases included patients receiving care in mainland France, including residents, travelers, and immigrants, as well as patients managed in French overseas territories in South America, the Indian Ocean, and Oceania. Parasite genotyping was performed using a standardized panel of 15 microsatellite markers. Complete genotypes were obtained for 1,269 cases, revealing 13 distinct genetic groups, including clonal lineages and non-clonal populations, alongside genotypes that could not be assigned to any recognized group. Type II strains predominated overall (82.6%) and were particularly frequent in congenital toxoplasmosis (869/955 cases, 91.0%). Despite being predominantly associated with infraclinical or mild congenital infections, type II strains were also responsible for severe congenital infections following maternal infection during all three trimesters of pregnancy, as well as acquired ocular toxoplasmosis. Haplogroup 16, encompassing strains previously assigned to multiple PCR-RFLP genotypes, showed an association with severe congenital toxoplasmosis, with six of seven cases presenting severe manifestations. Type I strains were remarkably rare (n = 5) and showed no signs of increased clinical severity compared to type II. Amazonian strains, another genetically diverse group, were identified almost exclusively in acquired toxoplasmosis in immunocompetent patients, all of them severe, in keeping with previous reports of the exceptional pathogenicity of this genetic group. In immunodeficient patients, Africa 1 strains (equivalent to ToxoDB#6) were more frequently associated with isolated cerebral toxoplasmosis (20/25 cases, 80%) than type II and type III strains. Overall, the results support that while a given T. gondii genetic group may be associated with a broad spectrum of clinical manifestations, significant differences in disease presentation exist between genetic groups. Conclusions/Significance This study constitutes the largest collection of human T. gondii genotypes linked to clinical data assembled to date and provides new insights, at a global level, into the relationships between parasite genetic diversity and clinical manifestations of toxoplasmosis. Our findings suggest a role for parasite genotype in shaping disease presentation, even in the context of strong host-related determinants such as immunodeficiency or gestational timing of infection. These results also highlight the value of long-term surveillance networks for understanding the epidemiology and pathogenicity of T. gondii on a global scale.