title: Alveolar macrophage-derived type I interferons orchestrate innate immunity to RSV through recruitment of antiviral monocytes.
abstract: Type I interferons (IFNs) are important for host defense from viral infections, acting to restrict viral production in infected cells and to promote antiviral immune responses. However, the type I IFN system has also been associated with severe lung inflammatory disease in response to respiratory syncytial virus (RSV). Which cells produce type I IFNs upon RSV infection and how this directs immune responses to the virus, and potentially results in pathological inflammation, is unclear. Here, we show that alveolar macrophages (AMs) are the major source of type I IFNs upon RSV infection in mice. AMs detect RSV via mitochondrial antiviral signaling protein (MAVS)-coupled retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs), and loss of MAVS greatly compromises innate immune restriction of RSV. This is largely attributable to loss of type I IFN-dependent induction of monocyte chemoattractants and subsequent reduced recruitment of inflammatory monocytes (infMo) to the lungs. Notably, the latter have potent antiviral activity and are essential to control infection and lessen disease severity. Thus, infMo recruitment constitutes an important and hitherto underappreciated, cell-extrinsic mechanism of type I IFN-mediated antiviral activity. Dysregulation of this system of host antiviral defense may underlie the development of RSV-induced severe lung inflammation.
authors.affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.
authors.forename: Michelle
authors.initials: M
authors.lastname: Goritzka
authors.affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.
authors.forename: Spyridon
authors.initials: S
authors.lastname: Makris
authors.affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.
authors.forename: Fahima
authors.initials: F
authors.lastname: Kausar
authors.affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.
authors.forename: Lydia R
authors.initials: LR
authors.lastname: Durant
authors.affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pereira
authors.affiliation: Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kumagai
authors.affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK.
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Culley
authors.affiliation: University Hospital Regensburg, 93042 Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.affiliation: Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Centre for Respiratory Infection, Respiratory Infections Section, National Heart and Lung Institute, Imperial College London, London W2 1PG, England, UK c.johansson@imperial.ac.uk.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Johansson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000818:Animals; D007113:Immunity, Innate; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000276:immunology; D011024:Pneumonia, Viral / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011956:Receptors, Cell Surface; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D000097905:Roundabout Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; C512612:MAVS protein, mouse; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins