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 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.