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

Cryptosporidium parvum subtypes differ in pathogenicity, but the underlying factors are largely unknown. We show that two genetically similar 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. This resistance was associated with a gene encoding a parasite ABC transporter and enhanced infectivity. Molecular analyses indicate that the ABC transporter belongs to a multidrug resistance protein (MRP) family. CpMRP1 binds bacterial metabolites, notably deoxycholic acid (DCA) that inhibits C. parvum growth. CpMRP1 is exported from small granules to the parasite-host interface, potentially mediating the export of xenobiotics. Loss of CpMRP1 reduces infectivity and DCA resistance in mice, and CpMRP1 polymorphisms across isolates determine susceptibility to DCA. These results define CpMRP1 as a determinant of C. parvum sensitivity to microbiome-mediated inhibition, thereby influencing infectivity.