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

Area of Science:

• Parasitology
• Microbiology
• Molecular Biology

Background:

• Cryptosporidium parvum exhibits varying pathogenicity among subtypes, with underlying mechanisms poorly understood.
• Differences in pathogenicity are not explained by in vitro growth rates between genetically similar isolates.

Purpose of the Study:

• To investigate the factors contributing to differential pathogenicity of Cryptosporidium parvum isolates.
• To identify parasite mechanisms involved in resistance to host microbiota-mediated inhibition.

Main Methods:

• Comparative in vitro growth assays of C. parvum isolates.
• Pathogenicity assessment in immunocompromised mice with and without antibiotic treatment.
• Molecular identification and characterization of a parasite ABC transporter (CpMRP1).
• Analysis of CpMRP1 binding to bacterial metabolites, including deoxycholic acid (DCA).
• Assessment of CpMRP1 function in parasite infectivity and DCA resistance in vivo.

Main Results:

• Avirulent C. parvum isolates showed reduced oocyst shedding, which was restored by antibiotic treatment, indicating microbiota influence.
• A parasite ABC transporter, CpMRP1 (belonging to the MRP family), was identified and associated with enhanced infectivity.
• CpMRP1 binds and potentially exports bacterial metabolites like DCA, which inhibits C. parvum growth.
• Loss of CpMRP1 function decreased parasite infectivity and DCA resistance in mice.
• CpMRP1 polymorphisms correlated with isolate susceptibility to DCA inhibition.

Conclusions:

• CpMRP1 is a key determinant of Cryptosporidium parvum sensitivity to microbiome-derived metabolites like DCA.
• CpMRP1 function influences parasite infectivity by mediating resistance to host colonization resistance.
• Understanding CpMRP1 and its interaction with the microbiota offers potential targets for controlling cryptosporidiosis.