Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice

Rudragouda Channappanavar; Anthony R Fehr; Rahul Vijay; Matthias Mack; Jincun Zhao; David K Meyerholz; Stanley Perlman

doi:10.1016/j.chom.2016.01.007

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Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice

Journal article

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Peer reviewed

Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice

Rudragouda Channappanavar, Anthony R Fehr, Rahul Vijay, Matthias Mack, Jincun Zhao, David K Meyerholz and Stanley Perlman

Cell host & microbe, Vol.19(2), pp.181-193

02/10/2016

DOI: 10.1016/j.chom.2016.01.007

PMCID: PMC4752723

PMID: 26867177

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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.

SARS Virus - immunology

Pneumonia - etiology

Severe Acute Respiratory Syndrome - virology

Humans

Severe Acute Respiratory Syndrome - complications

Severe Acute Respiratory Syndrome - immunology

Monocytes - immunology

Interferon Type I - immunology

Animals

Pneumonia - mortality

SARS Virus - genetics

Interferon Type I - genetics

Pneumonia - immunology

Severe Acute Respiratory Syndrome - genetics

Female

Mice

Mice, Inbred BALB C

SARS Virus - physiology

Macrophages - immunology

Pneumonia - genetics

Details

Title: Subtitle: Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice
Creators: Rudragouda Channappanavar - Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
Anthony R Fehr - Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
Rahul Vijay - Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242, USA
Matthias Mack - Department of Internal Medicine, University Hospital Regensburg, Regensburg 93042, Germany
Jincun Zhao - 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
David K Meyerholz - Department of Pathology, University of Iowa, Iowa City, IA 52242, USA
Stanley Perlman - 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
Resource Type: Journal article
Publication Details: Cell host & microbe, Vol.19(2), pp.181-193
DOI: 10.1016/j.chom.2016.01.007
PMID: 26867177
PMCID: PMC4752723
NLM abbreviation: Cell Host Microbe
ISSN: 1931-3128
eISSN: 1934-6069
Publisher: United States
Grant note: P01 AI060699 / NIAID NIH HHS R01 AI091322 / NIAID NIH HHS
Language: English
Date published: 02/10/2016
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
Record Identifier: 9983777476802771

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