eLife (Feb 2022)
Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
- Clare M Smith,
- Richard E Baker,
- Megan K Proulx,
- Bibhuti B Mishra,
- Jarukit E Long,
- Sae Woong Park,
- Ha-Na Lee,
- Michael C Kiritsy,
- Michelle M Bellerose,
- Andrew J Olive,
- Kenan C Murphy,
- Kadamba Papavinasasundaram,
- Frederick J Boehm,
- Charlotte J Reames,
- Rachel K Meade,
- Brea K Hampton,
- Colton L Linnertz,
- Ginger D Shaw,
- Pablo Hock,
- Timothy A Bell,
- Sabine Ehrt,
- Dirk Schnappinger,
- Fernando Pardo-Manuel de Villena,
- Martin T Ferris,
- Thomas R Ioerger,
- Christopher M Sassetti
Affiliations
- Clare M Smith
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States; Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
- Richard E Baker
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Megan K Proulx
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Bibhuti B Mishra
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States; Department of Immunology and Microbial Disease, Albany Medical College, Albany, United States
- Jarukit E Long
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Sae Woong Park
- ORCiD
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
- Ha-Na Lee
- ORCiD
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
- Michael C Kiritsy
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Michelle M Bellerose
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Andrew J Olive
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Kenan C Murphy
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Kadamba Papavinasasundaram
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Frederick J Boehm
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Charlotte J Reames
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- Rachel K Meade
- ORCiD
- Department of Molecular Genetics and Microbiology, Duke University, Durham, United States; University Program in Genetics and Genomics, Duke University, Durham, United States
- Brea K Hampton
- ORCiD
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, United States
- Colton L Linnertz
- ORCiD
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
- Ginger D Shaw
- ORCiD
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
- Pablo Hock
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
- Timothy A Bell
- ORCiD
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
- Sabine Ehrt
- ORCiD
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
- Dirk Schnappinger
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
- Fernando Pardo-Manuel de Villena
- ORCiD
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, United States
- Martin T Ferris
- ORCiD
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
- Thomas R Ioerger
- Department of Computer Science and Engineering, Texas A&M University, College Station, United States
- Christopher M Sassetti
- ORCiD
- Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
- DOI
- https://doi.org/10.7554/eLife.74419
- Journal volume & issue
-
Vol. 11
Abstract
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.
Keywords
