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

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

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 Supe...

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Main Authors: 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
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2021-06-01
Series:eLife
Subjects:
mycobacterium tuberculosis
legionella pneumophila
type i interferon
Online Access:https://elifesciences.org/articles/67290
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language English
format Article
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author 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
spellingShingle 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
Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons
eLife
mycobacterium tuberculosis
legionella pneumophila
type i interferon
author_facet 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
author_sort Daisy X Ji
title Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons
title_short Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons
title_full Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons
title_fullStr Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons
title_full_unstemmed Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferons
title_sort role of the transcriptional regulator sp140 in resistance to bacterial infections via repression of type i interferons
publisher eLife Sciences Publications Ltd
series eLife
issn 2050-084X
publishDate 2021-06-01
description 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.
topic mycobacterium tuberculosis
legionella pneumophila
type i interferon
url https://elifesciences.org/articles/67290
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spelling doaj-a13a048f3761473cb07137e4ffca8ea42021-07-01T16:53:35ZengeLife Sciences Publications LtdeLife2050-084X2021-06-011010.7554/eLife.67290Role of the transcriptional regulator SP140 in resistance to bacterial infections via repression of type I interferonsDaisy X Ji0https://orcid.org/0000-0002-9148-3620Kristen C Witt1https://orcid.org/0000-0001-8744-9457Dmitri I Kotov2https://orcid.org/0000-0001-7843-1503Shally R Margolis3Alexander Louie4Victoria Chevée5Katherine J Chen6Moritz M Gaidt7Harmandeep S Dhaliwal8Angus Y Lee9Stephen L Nishimura10Dario S Zamboni11https://orcid.org/0000-0002-7856-7512Igor Kramnik12https://orcid.org/0000-0001-6511-9246Daniel A Portnoy13K Heran Darwin14Russell E Vance15https://orcid.org/0000-0002-6686-3912Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision 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 StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesDivision 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 StatesDivision of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United StatesCancer Research Laboratory, University of California, Berkeley, Berkeley, United StatesCancer Research Laboratory, University of California, Berkeley, Berkeley, United StatesDepartment of Pathology, University of California, San Francisco, San Francisco, United StatesDepartment of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, BrazilThe National Emerging Infectious Diseases Laboratory, Department of Medicine (Pulmonary Center), and Department of Microbiology, Boston University School of Medicine, Boston, United StatesDivision 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 StatesDepartment of Microbiology, New York University Grossman School of Medicine, New York, United StatesDivision 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 StatesType 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.https://elifesciences.org/articles/67290mycobacterium tuberculosislegionella pneumophilatype i interferon

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