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Cell Host Microbe. 2016 Feb 10;19(2):181-93. doi: 10.1016/j.chom.2016.01.007.

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

Author information

1
Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
2
Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
3
Department of Internal Medicine, University Hospital Regensburg, Regensburg 93042, Germany.
4
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.
5
Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
6
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.

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.

Comment in

PMID:
26867177
PMCID:
PMC4752723
DOI:
10.1016/j.chom.2016.01.007
[Indexed for MEDLINE]
Free PMC Article

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