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.

SARS-CoV and IFN: Too Little, Too Late

“…In this issue of Cell Host & Microbe, Channappanavar et al (2016) use a SARS-coronavirus animal model to describe how rapid and robust virus replication with delayed IFN-I can lead to lung immunopathology, with fatal outcomes. In this issue of Cell Host & Microbe, Channappanavar et al (2016) use a SARS-coronavirus animal model to describe how rapid and robust virus replication with delayed IFN-I can lead to lung immunopathology, with fatal outcomes.…”

“…The work of Channappanavar et al (2016) in this issue of Cell Host & Microbe presents how SARS-CoV can cause exuberant inflammatory host responses with consequences of severe lung pathology. They used a murine model of SARS with a mouse-adapted SARS virus (ma-SARS-CoV) (Roberts et al, 2007) and observed fast and robust virus replication accompanied by a delayed IFN-I response in BALB/c mice.…”

Epidemic and Emerging Coronaviruses (Severe Acute Respiratory Syndrome and Middle East Respiratory Syndrome)

“…26 In another study of mice infected with SARS-CoV, robust virus replication accompanied by delayed type I IFN (IFN-I) signaling was observed orchestrating inflammatory responses and lung immunopathology with reduced survival. 27 Casecontrol studies have suggested that genetic variants of IL-12 receptor B1 predispose to SARS-CoV infection, 28 whereas Mannosebinding lectin deficiency is a susceptibility factor for acquisition of SARS-CoV infection. 29 Lung histopathology in patients with severe SARS-CoV infection include DAD, denudation of bronchial epithelia, loss of cilia, squamous metaplasia, and giant cell infiltrate, with a marked increase in macrophages in the alveoli and the interstitium.…”

Pleiotropic Roles of Type 1 Interferons in Antiviral Immune Responses

“…This study provocatively suggests that IFN-I signaling is dispensable for controlling SARS-CoV replication in vivo. Recently, an important study was published where the authors further highlighted the importance of IFN-I signaling in respiratory virus pathology by reporting that delayed IFN-I induction and signaling during SARS-CoV infection in mice promoted the development and infiltration of inflammatory monocyte-macrophages into the lung, resulting in exacerbated lung pathology and lethal pneumonia (Channappanavar et al, 2016). Attenuation of IFN-I signaling either through genetic deletion or through antibody neutralization of IFNAR1 prevented inflammatory monocyte-macrophage infiltration into the lung, abrogated lung immune pathology, and resulted in mild clinical disease.…”