title: Type I IFN Inhibits Alternative Macrophage Activation during Mycobacterium tuberculosis Infection and Leads to Enhanced Protection in the Absence of IFN-γ Signaling.
abstract: Tuberculosis causes ∼1.5 million deaths every year, thus remaining a leading cause of death from infectious diseases in the world. A growing body of evidence demonstrates that type I IFN plays a detrimental role in tuberculosis pathogenesis, likely by interfering with IFN-γ-dependent immunity. In this article, we reveal a novel mechanism by which type I IFN may confer protection against Mycobacterium tuberculosis infection in the absence of IFN-γ signaling. We show that production of type I IFN by M. tuberculosis-infected macrophages induced NO synthase 2 and inhibited arginase 1 gene expression. In vivo, absence of both type I and type II IFN receptors led to strikingly increased levels of arginase 1 gene expression and protein activity in infected lungs, characteristic of alternatively activated macrophages. This correlated with increased lung bacterial burden and pathology and decreased survival compared with mice deficient in either receptor. Increased expression of other genes associated with alternatively activated macrophages, as well as increased expression of Th2-associated cytokines and decreased TNF expression, were also observed. Thus, in the absence of IFN-γ signaling, type I IFN suppressed the switching of macrophages from a more protective classically activated phenotype to a more permissive alternatively activated phenotype. Together, our data support a model in which suppression of alternative macrophage activation by type I IFN during M. tuberculosis infection, in the absence of IFN-γ signaling, contributes to host protection.
authors.affiliation: Microbiology and Infection Research Domain, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, and Life and Health Sciences Research Institute/3B's PT Government Associate Laboratory, 4710 Braga/Guimarães, Portugal; lucia.teixeira@crick.ac.uk.|Laboratory of Immunoregulation and Infection, The Francis Crick Institute, London NW1 1AT, United Kingdom.
authors.forename: Lúcia
authors.identifier: 0000-0002-4817-8196
authors.initials: L
authors.lastname: Moreira-Teixeira
authors.affiliation: Microbiology and Infection Research Domain, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, and Life and Health Sciences Research Institute/3B's PT Government Associate Laboratory, 4710 Braga/Guimarães, Portugal.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200 Porto, Portugal.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sousa
authors.affiliation: Laboratory of Immunoregulation and Infection, The Francis Crick Institute, London NW1 1AT, United Kingdom.
authors.forename: Finlay W
authors.initials: FW
authors.lastname: McNab
authors.affiliation: Microbiology and Infection Research Domain, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, and Life and Health Sciences Research Institute/3B's PT Government Associate Laboratory, 4710 Braga/Guimarães, Portugal.
authors.forename: Egídio
authors.identifier: 0000-0002-7462-8234
authors.initials: E
authors.lastname: Torrado
authors.affiliation: Microbiology and Infection Research Domain, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, and Life and Health Sciences Research Institute/3B's PT Government Associate Laboratory, 4710 Braga/Guimarães, Portugal.
authors.forename: Filipa
authors.identifier: 0000-0003-2618-5093
authors.initials: F
authors.lastname: Cardoso
authors.affiliation: Microbiology and Infection Research Domain, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, and Life and Health Sciences Research Institute/3B's PT Government Associate Laboratory, 4710 Braga/Guimarães, Portugal.
authors.forename: Henrique
authors.identifier: 0000-0001-6188-2535
authors.initials: H
authors.lastname: Machado
authors.affiliation: Microbiology and Infection Research Domain, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, and Life and Health Sciences Research Institute/3B's PT Government Associate Laboratory, 4710 Braga/Guimarães, Portugal.
authors.forename: Flávia
authors.identifier: 0000-0002-2273-2806
authors.initials: F
authors.lastname: Castro
authors.affiliation: Microbiology and Infection Research Domain, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, and Life and Health Sciences Research Institute/3B's PT Government Associate Laboratory, 4710 Braga/Guimarães, Portugal.
authors.forename: Vânia
authors.identifier: 0000-0002-8029-2191
authors.initials: V
authors.lastname: Cardoso
authors.affiliation: Microbiology and Infection Research Domain, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, and Life and Health Sciences Research Institute/3B's PT Government Associate Laboratory, 4710 Braga/Guimarães, Portugal.
authors.forename: Joana
authors.identifier: 0000-0001-7306-7378
authors.initials: J
authors.lastname: Gaifem
authors.affiliation: Laboratory of Immunoregulation and Infection, The Francis Crick Institute, London NW1 1AT, United Kingdom.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200 Porto, Portugal.|Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050 Porto, Portugal.
authors.forename: Rui
authors.identifier: 0000-0002-9447-0665
authors.initials: R
authors.lastname: Appelberg
authors.affiliation: Microbiology and Infection Research Domain, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, and Life and Health Sciences Research Institute/3B's PT Government Associate Laboratory, 4710 Braga/Guimarães, Portugal.
authors.forename: António Gil
authors.initials: AG
authors.lastname: Castro
authors.affiliation: Laboratory of Immunoregulation and Infection, The Francis Crick Institute, London NW1 1AT, United Kingdom.|National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW3 6NP, United Kingdom; and.
authors.forename: Anne
authors.identifier: 0000-0001-9845-6134
authors.initials: A
authors.lastname: O'Garra
authors.affiliation: Microbiology and Infection Research Domain, Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, and Life and Health Sciences Research Institute/3B's PT Government Associate Laboratory, 4710 Braga/Guimarães, Portugal.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200 Porto, Portugal.|Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150 Porto, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Saraiva
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D058491:Bacterial Load; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
chemical_list: D016207:Cytokines; D007370:Interferon Type I; D017471:Receptors, Interferon; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase