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

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)181-193
Number of pages13
JournalCell Host and Microbe
Volume19
Issue number2
DOIs
StatePublished - Jan 1 2016

Fingerprint

Severe Acute Respiratory Syndrome
Interferon Type I
Monocytes
Pneumonia
Macrophages
Lung
Coronavirus
Viral Load
Viruses
Acute Disease
Virus Replication
Infection
Chemokines
Blood Vessels
Pathology
Cytokines
Survival
Therapeutics

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Virology

Cite this

Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. / Channappanavar, Rudragouda; Fehr, Anthony R.; Vijay, Rahul; Mack, Matthias; Zhao, Jincun; Meyerholz, David K.; Perlman, Stanley.

In: Cell Host and Microbe, Vol. 19, No. 2, 01.01.2016, p. 181-193.

Research output: Contribution to journalArticle

Channappanavar, Rudragouda ; Fehr, Anthony R. ; Vijay, Rahul ; Mack, Matthias ; Zhao, Jincun ; Meyerholz, David K. ; Perlman, Stanley. / Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. In: Cell Host and Microbe. 2016 ; Vol. 19, No. 2. pp. 181-193.
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