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

  1. Clare M Smith  Is a corresponding author
  2. Richard E Baker
  3. Megan K Proulx
  4. Bibhuti B Mishra
  5. Jarukit E Long
  6. Sae Woong Park
  7. Ha-Na Lee
  8. Michael C Kiritsy
  9. Michelle M Bellerose
  10. Andrew J Olive
  11. Kenan C Murphy
  12. Kadamba Papavinasasundaram
  13. Frederick J Boehm
  14. Charlotte J Reames
  15. Rachel K Meade
  16. Brea K Hampton
  17. Colton L Linnertz
  18. Ginger D Shaw
  19. Pablo Hock
  20. Timothy A Bell
  21. Sabine Ehrt
  22. Dirk Schnappinger
  23. Fernando Pardo-Manuel de Villena
  24. Martin T Ferris
  25. Thomas R Ioerger
  26. Christopher M Sassetti  Is a corresponding author
  1. Duke University, United States
  2. University of Massachusetts Medical School, United States
  3. Weill Cornell Medical College, United States
  4. Michigan State University, United States
  5. University of North Carolina at Chapel Hill, United States
  6. 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

The following data sets were generated

Article and author information

Author details

  1. Clare M Smith

    Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
    For correspondence
    clare.m.smith@duke.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2601-0955
  2. Richard E Baker

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Megan K Proulx

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Bibhuti B Mishra

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jarukit E Long

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sae Woong Park

    Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ha-Na Lee

    Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4136-0128
  8. Michael C Kiritsy

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8364-8088
  9. Michelle M Bellerose

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0232-9953
  10. Andrew J Olive

    Microbiology and Molecular Genetics, Michigan State University, East Lansing, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3441-3113
  11. Kenan C Murphy

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Kadamba Papavinasasundaram

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Frederick J Boehm

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1644-5931
  14. Charlotte J Reames

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Rachel K Meade

    Department of Molecular Genetics and Microbiology, Duke University, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Brea K Hampton

    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7167-5652
  17. Colton L Linnertz

    Department of Genetics, University of North Carolina at Chapel Hill, Morrisville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2969-8193
  18. Ginger D Shaw

    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Pablo Hock

    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Timothy A Bell

    Department of Genetics,, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Sabine Ehrt

    Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7951-2310
  22. Dirk Schnappinger

    Department of Microbiology and Immunology, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Fernando Pardo-Manuel de Villena

    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Martin T Ferris

    Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Thomas R Ioerger

    Department of Computer Science and Engineering, Texas A&M University, College Station, United States
    Competing interests
    The authors declare that no competing interests exist.
  26. Christopher M Sassetti

    Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United States
    For correspondence
    christopher.sassetti@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6178-4329

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

  1. 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

  1. Preprint posted: December 1, 2020 (view preprint)
  2. Received: October 4, 2021
  3. Accepted: January 27, 2022
  4. Accepted Manuscript published: February 3, 2022 (version 1)
  5. 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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  1. Clare M Smith
  2. Richard E Baker
  3. Megan K Proulx
  4. Bibhuti B Mishra
  5. Jarukit E Long
  6. Sae Woong Park
  7. Ha-Na Lee
  8. Michael C Kiritsy
  9. Michelle M Bellerose
  10. Andrew J Olive
  11. Kenan C Murphy
  12. Kadamba Papavinasasundaram
  13. Frederick J Boehm
  14. Charlotte J Reames
  15. Rachel K Meade
  16. Brea K Hampton
  17. Colton L Linnertz
  18. Ginger D Shaw
  19. Pablo Hock
  20. Timothy A Bell
  21. Sabine Ehrt
  22. Dirk Schnappinger
  23. Fernando Pardo-Manuel de Villena
  24. Martin T Ferris
  25. Thomas R Ioerger
  26. Christopher M Sassetti
(2022)
Host-pathogen genetic interactions underlie tuberculosis susceptibility in genetically diverse mice
eLife 11:e74419.
https://doi.org/10.7554/eLife.74419

Share this article

https://doi.org/10.7554/eLife.74419

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