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

The outcome of an encounter with Mycobacterium tuberculosis (Mtb) depends on interactions between the heterogeneous immune response of the host and the ability of the pathogen to adapt. Understanding this interplay has proven difficult, largely because experimentally tractable small animal models do not recapitulate the heterogenous disease observed in natural infections. We leveraged the genetically diverse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to associate 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 responses. Global analysis of Mtb mutant fitness across the CC panel revealed that a large fraction of the pathogens genome that is necessary for adaptation to diverse host microenvironments. Both immunological and bacterial traits were associated genetic variants distributed across the mouse genome, elucidating the complex genetic landscape that underlies host-pathogen interactions in a diverse population.