Deciphering Virulence Determinants of Human-Pathogenic Atypical Toxoplasma gondii

About This Grant

1 PROJECT SUMMARY 2 3 Apicomplexan parasites are a major cause of mortality and morbidity in humans and animals. As a 4 model apicomplexan parasite, Toxoplasma gondii is highlighted by the CDC as the 2nd leading cause of 5 foodborne illness in the US and is classified as an NIAID Emerging/Re-emerging Pathogen. While life- 6 threatening diseases can occur in immunocompromised individuals and fetuses, infections caused by clonal 7 strains frequently found in Europe and North America are mostly benign in healthy humans. However, severe 8 toxoplasmosis outbreaks with fatal consequences among healthy individuals have been documented in South 9 America, where a variety of non-clonal genetically heterogeneous Toxoplasma strains with distinct virulent 10 features are prevalent. To date, the virulence characteristics and parasite genes responsible for the 11 pathogenicity of such Toxoplasma strains in humans remain largely unknown. 12 This project focuses on the virulence traits of human-pathogenic, atypical Toxoplasma strains in the 13 laboratory rat model and aims to understand the genomic basis of pathogenicity and identify genes 14 determining the parasite virulence. The proposal is organized into two specific aims: 1) to elucidate the 15 pathogenic potential of these atypical Toxoplasma strains in the rat model in vivo enabling downstream 16 phylogenetic analysis of known virulence factor and facilitating comparastive genome analysis to detect 17 additional virulence determinants; 2) to utilize a CRISPR/Cas9-based functional genomic screening approach, 18 both in vivo and in vitro, to uncover novel virulence factors in one atypical Toxoplasma strain associated with 19 human fatality. Collectively, the completion of this project will provide novel insight into the molecular basis of 20 high-pathogenic Toxoplasma outbreaks in the human population and contribute to building the scientific 21 framework for the development of therapeutic strategies against acute toxoplasmosis.