Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice

By Rudragouda Channappanavar, Anthony R. Fehr, R. Vijay, M. Mack, Jincun Zhao, D. Meyerholz, S. Perlman. Cell Host and Microbe, 2016

1,383 citations recorded by the source corpus.

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.

Subfields: Infectious Diseases, Neurology

View Paper: https://www.semanticscholar.org/paper/69e1ed93051bb5ba03ff2cbce19409a54279199f

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Citations in the corpus

Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection. (2019, background): “In patients who eventually died of SARS (hereafter referred to as deceased patients) and animal models, extensive lung damage is associated with high initial viral loads, increased IMM accumulation in the lungs, and elevated serum proinflammatory cytokine (IL-1, IL-6, IL-8, CXCL-10, and MCP1) levels”
Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients (2020, background): “This analysis provides timely information for understanding SARS- CoV-2-host interactions and COVID-19 pathogenesis. ll ll”
Molecular Mechanism of SARS-CoVs Orf6 Targeting the Rae1–Nup98 Complex to Compete With mRNA Nuclear Export (2022, background): “Accumulating evidence indicates that dysregulated innate immune response is assigned an important role in the pathogenesis of highly pathogenic coronaviruses such as SARS-CoV-1 and Middle East respiratory syndrome coronaviruse (MERS-CoV) (Cameron et al., 2007; Channappanavar et al., 2016; Channappan”
Cytokine Storm in COVID-19: The Current Evidence and Treatment Strategies (2020, background): “In the aspects of murine models of coronavirus, infection with SARS-CoV in BALB/c mice has been shown to induce an increase in the number of pathogenic inflammatory monocyte– macrophages (IMMs) (34).”
Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients (2020, methodology): “tome, leading to aberrant host cell metabolism and modulated immune response which is ideal for viral replication [12,33].”
SARS-CoV-2: A Storm is Raging. (2020, positive): “…SARS-CoV infection, it was immune dysregulation, rather than the level of peak viremia, which induced insufficient type-I interferon (IFN) response (too-little-and-too-late), aberrant proinflammatory cytokine secretion by alveolar macrophages and subsequent CD4 + and CD8 + T cell dysfunction (17).”
Sex-based differences in susceptibility to SARS-CoV infection (2017, methodology): “Intracellular cytokine staining was carried out using a previously described protocol (16).”
Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology (2017, background): “These cells are the predominant source of cytokines and chemokines associated with hCoV lethal disease observed both in humans and animal models [38, 32].”
SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues (2020, positive): “Whether type I IFNs are net protective or detrimental to the host might depend on the stage of infection; cell subsets in question; the SARS viral clade (Channappanavar et al., 2016; Channappanavar et al., 2019; Channappanavar and Perlman, 2017; Davidson et al., 2015); and other factors such as co-i”