Cryptosporidium parvum multidrug resistance protein confers resistance to toxic gut microbial metabolite

Cryptosporidium parvum subtypes differ in pathogenicity, but the genetic factors underlying these differences are largely unknown. Here, we show that two C. parvum isolates grow equally well in vitro but differ in pathogenicity in immunocompromised mice. Reduced oocyst shedding of the avirulent strain was restored by antibiotic treatment, suggesting susceptibility to colonization resistance imparted by the microbiota. To investigate the extent of genetic differences of the isolates, we comducted whole genome sequencing (WGS). To map significant associations between parasite genes and enhanced infectivity of the virulent strain, we performed genetic crosses followed by bulk segregant analysis (BSA) under permissive (antibiotic-treated) and restrictive (untreated) conditions. To evaluate the environmental differences between these conditions, we also profiled gut microbiota composition using 16S rRNA sequencing.