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

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

Elife. 2021 Jun 21:10:e67290. doi: 10.7554/eLife.67290.

Authors

Daisy X Ji^#¹, Kristen C Witt^#¹, Dmitri I Kotov^{1

2}, Shally R Margolis¹, Alexander Louie¹, Victoria Chevée¹, Katherine J Chen^{1

2}, Moritz M Gaidt¹, Harmandeep S Dhaliwal³, Angus Y Lee³, Stephen L Nishimura⁴, Dario S Zamboni⁵, Igor Kramnik⁶, Daniel A Portnoy^{1

7

8}, K Heran Darwin⁹, Russell E Vance^{1

2

3}

Affiliations

¹ Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
² Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States.
³ Cancer Research Laboratory, University of California, Berkeley, Berkeley, United States.
⁴ Department of Pathology, University of California, San Francisco, San Francisco, United States.
⁵ Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
⁶ The National Emerging Infectious Diseases Laboratory, Department of Medicine (Pulmonary Center), and Department of Microbiology, Boston University School of Medicine, Boston, United States.
⁷ Division of Biochemistry, Biophysics and Structural Biology, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
⁸ Department of Plant and Microbial Biology, University of California, Berkeley, Berkeley, United States.
⁹ Department of Microbiology, New York University Grossman School of Medicine, New York, United States.

^# Contributed equally.

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 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.

Keywords: immunology; inflammation; legionella pneumophila; mouse; mycobacterium tuberculosis; type i interferon.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Bacterial Infections / immunology*
Female
Gene Expression Regulation / drug effects
Interferon Type I / genetics
Interferon Type I / metabolism*
Macrophages / physiology
Male
Mice
Mice, Knockout
Minor Histocompatibility Antigens / genetics
Minor Histocompatibility Antigens / metabolism
Mycobacterium tuberculosis
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Receptor, Interferon alpha-beta / genetics
Receptor, Interferon alpha-beta / metabolism
Specific Pathogen-Free Organisms
Transcription Factors / genetics
Transcription Factors / metabolism*
Tumor Necrosis Factor-alpha / pharmacology

Substances

Ifnar1 protein, mouse
Interferon Type I
Minor Histocompatibility Antigens
Nuclear Proteins
Sp110 protein, mouse
Transcription Factors
Tumor Necrosis Factor-alpha
Receptor, Interferon alpha-beta

Associated data

GEO/GSE166114

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding