Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice

The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on the pathogen's ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterogeneity of tuberculosis disease. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to create a resource for associating bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and produce qualitatively distinct immune states. Global analysis of Mtb transposon mutant fitness (TnSeq) across the CC panel revealed that many virulence pathways are only required in specific host microenvironments, identifying a large fraction of the pathogen's genome that has been maintained to ensure fitness in a diverse population. Both immunological and bacterial traits can be associated with genetic variants distributed across the mouse genome, making the CC a unique population for identifying specific host-pathogen genetic interactions that influence pathogenesis.

Automated summary

This study utilizes a genetically diverse Collaborative Cross mouse panel and a library of Mtb mutants to investigate the relationship between bacterial genetic requirements and host genetics and immunity. Global analysis reveals that many virulence pathways are only required in specific host microenvironments, and a large portion of the pathogen's genome has been maintained for fitness in a diverse population. The study identifies genetic variants across the mouse genome that are associated with both immunological and bacterial traits, providing a unique population for studying specific host-pathogen genetic interactions that influence pathogenesis.