Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons

  1. Daisy X Ji
  2. Kristen C Witt
  3. Dmitri I Kotov
  4. Shally R Margolis
  5. Alexander Louie
  6. Victoria Chevée
  7. Katherine J Chen
  8. Moritz Gaidt
  9. Harmandeep S Dhaliwal
  10. Angus Y Lee
  11. Stephen L Nishimura
  12. Dario S Zamboni
  13. Igor Kramnik
  14. Daniel A. Portnoy
  15. K Heran Darwin
  16. Russell E Vance  Is a corresponding author
  1. UC Berkeley, United States
  2. University of California, Berkeley, United States
  3. University of California at San Francisco, United States
  4. University of São Paulo, Brazil
  5. Boston University, Boston University School of Medicine, United States
  6. New York University Robert Grossman School of Medicine, United States

Abstract

Type I interferons (IFNs) are essential for anti-viral immunity, but often impair protective immune responses during bacterial infections. An important question is how type I IFNs are strongly induced during viral infections, and yet are appropriately restrained during bacterial infections. The Super susceptibility to tuberculosis 1 (Sst1) locus in mice confers resistance to diverse bacterial infections. Here we provide evidence that Sp140 is a gene encoded within the Sst1 locus that represses type I IFN transcription during bacterial infections. We generated Sp140-/- mice and find they are susceptible to infection by Legionella pneumophila and Mycobacterium tuberculosis. Susceptibility of Sp140-/- mice to bacterial infection was rescued by crosses to mice lacking the type I IFN receptor (Ifnar-/-). Our results implicate Sp140 as an important negative regulator of type I IFNs that is essential for resistance to bacterial infections.

Data availability

RNA-seq data is available at GEO, accession number GSE166114. Amplicon sequencing data is available at the SRA, BioProject accession number PRJNA698382

The following data sets were generated

Article and author information

Author details

  1. Daisy X Ji

    Molecular and Cell Biology, UC Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  2. Kristen C Witt

    Molecular and Cell Biology, UC Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8744-9457
  3. Dmitri I Kotov

    Molecular and Cell Biology, UC Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7843-1503
  4. Shally R Margolis

    Molecular and Cell Biology, UC Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  5. Alexander Louie

    Molecular and Cell Biology, UC Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  6. Victoria Chevée

    Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  7. Katherine J Chen

    Molecular and Cell Biology, UC Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  8. Moritz Gaidt

    Molecular and Cell Biology, UC Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  9. Harmandeep S Dhaliwal

    Cancer Research Laboratory, UC Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  10. Angus Y Lee

    Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  11. Stephen L Nishimura

    Pathology, University of California at San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  12. Dario S Zamboni

    Cell Biology, University of São Paulo, Ribeirão Preto, Brazil
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7856-7512
  13. Igor Kramnik

    The National Emerging Infectious Diseases Laboratories, Department of Medicine, Boston University, Boston University School of Medicine, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6511-9246
  14. Daniel A. Portnoy

    Cancer Research Laboratory, UC Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  15. K Heran Darwin

    Department of Microbiology, New York University Robert Grossman School of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  16. Russell E Vance

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    rvance@berkeley.edu
    Competing interests
    Russell E Vance, consults for Ventus Therapeutics.Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6686-3912

Funding

National Institutes of Health (R37AI075039)

  • Russell E Vance

National Institutes of Health (R01AI155634)

  • Russell E Vance

Howard Hughes Medical Institute (Investigator Award)

  • Russell E Vance

National Institutes of Health (P01AI066302)

  • Russell E Vance

National Institutes of Health (P01AI066302)

  • Daniel A. Portnoy

National Institutes of Health (R01HL134183)

  • Stephen L Nishimura

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Christina L Stallings, Washington University School of Medicine, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animal studies were approved by the UC Berkeley Animal Care and Use Committee (current protocol number: AUP-2014-09-6665-2).

Version history

  1. Received: February 6, 2021
  2. Accepted: June 20, 2021
  3. Accepted Manuscript published: June 21, 2021 (version 1)
  4. Version of Record published: July 1, 2021 (version 2)

Copyright

© 2021, Ji 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. Daisy X Ji
  2. Kristen C Witt
  3. Dmitri I Kotov
  4. Shally R Margolis
  5. Alexander Louie
  6. Victoria Chevée
  7. Katherine J Chen
  8. Moritz Gaidt
  9. Harmandeep S Dhaliwal
  10. Angus Y Lee
  11. Stephen L Nishimura
  12. Dario S Zamboni
  13. Igor Kramnik
  14. Daniel A. Portnoy
  15. K Heran Darwin
  16. Russell E Vance
(2021)
Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons
eLife 10:e67290.
https://doi.org/10.7554/eLife.67290

Share this article

https://doi.org/10.7554/eLife.67290

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