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

eLife, Volume: 11
February 3, 2022
Clare M Smith CM, Richard E Baker RE, Megan K Proulx MK, Bibhuti B Mishra BB, Jarukit E Long JE, Sae Woong Park SW, Ha-Na Lee HN, Michael C Kiritsy MC, Michelle M Bellerose MM, Andrew J Olive AJ, Kenan C Murphy KC, Kadamba Papavinasasundaram K, Frederick J Boehm FJ, Charlotte J Reames CJ, Rachel K Meade RK, Brea K Hampton BK, Colton L Linnertz CL, Ginger D Shaw GD, Pablo Hock P, Timothy A Bell TA, Sabine Ehrt S, Dirk Schnappinger D, Fernando Pardo-Manuel de Villena F, Martin T Ferris MT, Thomas R Ioerger TR, Christopher M Sassetti CM

The outcome of an encounter with () 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 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 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.