title: Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice.
abstract: Highly pathogenic human respiratory coronaviruses cause acute lethal disease characterized by exuberant inflammatory responses and lung damage. However, the factors leading to lung pathology are not well understood. Using mice infected with SARS (severe acute respiratory syndrome)-CoV, we show that robust virus replication accompanied by delayed type I interferon (IFN-I) signaling orchestrates inflammatory responses and lung immunopathology with diminished survival. IFN-I remains detectable until after virus titers peak, but early IFN-I administration ameliorates immunopathology. This delayed IFN-I signaling promotes the accumulation of pathogenic inflammatory monocyte-macrophages (IMMs), resulting in elevated lung cytokine/chemokine levels, vascular leakage, and impaired virus-specific T cell responses. Genetic ablation of the IFN-αβ receptor (IFNAR) or IMM depletion protects mice from lethal infection, without affecting viral load. These results demonstrate that IFN-I and IMM promote lethal SARS-CoV infection and identify IFN-I and IMMs as potential therapeutic targets in patients infected with pathogenic coronavirus and perhaps other respiratory viruses.
authors: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
authors: Rudragouda
authors: R
authors: Channappanavar
authors: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
authors: Anthony R
authors: AR
authors: Fehr
authors: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
authors: Rahul
authors: R
authors: Vijay
authors: Department of Internal Medicine, University Hospital Regensburg, Regensburg 93042, Germany.
authors: Matthias
authors: M
authors: Mack
authors: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA; State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
authors: Jincun
authors: J
authors: Zhao
authors: Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
authors: David K
authors: DK
authors: Meyerholz
authors: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: stanley-perlman@uiowa.edu.
authors: Stanley
authors: S
authors: Perlman
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology*; D011014:Pneumonia / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000401:mortality*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D045169:Severe Acute Respiratory Syndrome / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000821:virology
chemical_list: D007370:Interferon Type I