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

Daisy X Ji; Kristen C Witt; Dmitri I Kotov; Shally R Margolis; Alexander Louie; Victoria Chevée; Katherine J Chen; Moritz M Gaidt; Harmandeep S Dhaliwal; Angus Y Lee; Stephen L Nishimura; Dario S Zamboni; Igor Kramnik; Daniel A Portnoy; K Heran Darwin; Russell E Vance

doi:10.7554/eLife.67290

eLife (Jun 2021)

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

Daisy X Ji,
Kristen C Witt,
Dmitri I Kotov,
Shally R Margolis,
Alexander Louie,
Victoria Chevée,
Katherine J Chen,
Moritz M Gaidt,
Harmandeep S Dhaliwal,
Angus Y Lee,
Stephen L Nishimura,
Dario S Zamboni,
Igor Kramnik,
Daniel A Portnoy,
K Heran Darwin,
Russell E Vance

Affiliations

Daisy X Ji: ORCiD; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Kristen C Witt: ORCiD; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Dmitri I Kotov: ORCiD; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
Shally R Margolis: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Alexander Louie: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Victoria Chevée: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Katherine J Chen: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
Moritz M Gaidt: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
Harmandeep S Dhaliwal: Cancer Research Laboratory, University of California, Berkeley, Berkeley, United States
Angus Y Lee: Cancer Research Laboratory, University of California, Berkeley, Berkeley, United States
Stephen L Nishimura: Department of Pathology, University of California, San Francisco, San Francisco, United States
Dario S Zamboni: ORCiD; Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
Igor Kramnik: ORCiD; The National Emerging Infectious Diseases Laboratory, Department of Medicine (Pulmonary Center), and Department of Microbiology, Boston University School of Medicine, Boston, United States
Daniel A Portnoy: Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Division of Biochemistry, Biophysics and Structural Biology, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, United States
K Heran Darwin: Department of Microbiology, New York University Grossman School of Medicine, New York, United States
Russell E Vance: ORCiD; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States; Cancer Research Laboratory, University of California, Berkeley, Berkeley, United States

DOI: https://doi.org/10.7554/eLife.67290
Journal volume & issue: Vol. 10

Abstract

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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 found that 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.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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