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Rudragouda Channappanavar, Anthony Fehr, Rahul Vijay, Zhao Jincun, David K Meyerholz, Stanley Perlman, Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice, The Journal of Immunology, Volume 196, Issue 1_Supplement, May 2016, Page 63.10, https://doi.org/10.4049/jimmunol.196.Supp.63.10
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Abstract
Highly pathogenic human respiratory coronaviruses cause acute lethal disease characterized by an exuberant inflammatory response and severe lung damage. Although fatal outcomes due to immunopathological events following SARS-CoV infection have been well established, factors initiating detrimental inflammatory responses are not well understood. Since persistent elevation of IFN-I suggested a pathogenic role in SARS patients, we explored the possibility that IFN-I was critical in the initiation of events that led to lethal lung immunopathology. Using mice infected with SARS (Severe Acute Respiratory Syndrome)-CoV, we show that robust virus replication accompanied by dysregulated type I interferon (IFN-I) signaling orchestrated exuberant inflammatory responses and lung immunopathology with diminished survival. Delayed IFN-I signaling promoted the accumulation of pathogenic inflammatory monocyte-macrophages (IMMs) resulting in elevated lung inflammatory cytokine/chemokine levels, extensive vascular leakage and impaired virus-specific T cell responses. Genetic ablation of the IFN-αβ receptor (IFNAR) or depletion of IMMs completely protected mice from lethal infection, without affecting viral load. Together, these results demonstrate that IFN-I signaling is detrimental in highly susceptible SARS-CoV-infected BALB/c mice, in large part by promoting the influx of highly pathogenic inflammatory monocytes-macrophages (IMMs) and identify IFN-I and IMMs as potential therapeutic targets in patients infected with severe CoV and perhaps other highly pathogenic respiratory viruses.
