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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Smith, CM; Baker, RE; Proulx, MK; Mishra, BB; Long, JE; Park, SW; Lee, H-N; Kiritsy, MC; Bellerose, MM; Olive, AJ; Murphy, KC; Papavinasasundaram, K; Boehm, FJ; Reames, CJ; Meade, RK; Hampton, BK; Linnertz, CL; Shaw, GD; Hock, P; Bell, TA; Ehrt, S; Schnappinger, D; Pardo-Manuel de Villena, F; Ferris, MT; Ioerger, TR; Sassetti, CM

Published Date

  • February 3, 2022

Published In

Volume / Issue

  • 11 /

PubMed ID

  • 35112666

Pubmed Central ID

  • PMC8846590

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/eLife.74419

Language

  • eng

Conference Location

  • England