Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
- Duke University, United States
- University of Massachusetts Medical School, United States
- Weill Cornell Medical College, United States
- Michigan State University, United States
- University of North Carolina at Chapel Hill, United States
- Texas A&M University, United States
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.
Data availability
All relevant data to support the findings of this study are located within the paper and supplemental files. Genome sequence data is deposited in the NCBI Gene Expression Omnibus (GEO), accession number GSE164156. All raw phenotype values and QTL mapping objects are located on GitHub @sassettilab in the Smith_et_al_CC_TnSeq repository
Article and author information
Author details
Michelle M Bellerose
Christopher M Sassetti
Funding
National Institute of Allergy and Infectious Diseases (AI132130)
- Fernando Pardo-Manuel de Villena
- Christopher M Sassetti
National Institute of Allergy and Infectious Diseases (U19AI100625)
- Fernando Pardo-Manuel de Villena
- Martin T Ferris
Howard Hughes Medical Institute (A20-0146)
- Brea K Hampton
National Human Genome Research Institute (U24HG010100)
- Fernando Pardo-Manuel de Villena
Bank of America (Charles H King Postdoctoral Fellowship)
- Clare M Smith
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Bavesh D Kana, University of the Witwatersrand, South Africa
Ethics
Animal experimentation: Mouse studies were performed in strict accordance using the recommendations from the Guide for the Care and Use of Laboratory Animals of the National Institute of Health and the Office of Laboratory Animal Welfare. Mouse studies at the University of Massachusetts Medical School (UMASS) were performed using protocols approved by the UMASS Institutional Animal Care and Use Committee (IACUC) (Animal Welfare Assurance Number A3306-01) in a manner designed to minimize pain and suffering in Mtb-infected animals. Any animal that exhibited severe disease signs was immediately euthanized in accordance with IACUC approved endpoints. All mouse studies at UNC (Animal Welfare Assurance #A3410-01) were performed using protocols approved by the UNC Institutional Animal Care and Use Committee (IACUC).
Version history
- Preprint posted: December 1, 2020 (view preprint)
- Received: October 4, 2021
- Accepted: January 27, 2022
- Accepted Manuscript published: February 3, 2022 (version 1)
- Version of Record published: February 15, 2022 (version 2)
Copyright
© 2022, Smith et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
eLife 11:e74419.
https://doi.org/10.7554/eLife.74419
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