TYPE I INTERFERON-DEPENDENT CELLULAR REMODELING DURING ACUTE PULMONARY MHV INFECTION

Abstract

Impaired type I interferon (IFN) responses are predictive of severe disease during pulmonary coronavirus infection. In the periphery, dampened IFN-responsiveness is associated with viremia and hypercytokinemia, however the resolution of IFN-dependent innate immune responses in the lungs remains limited. Here, we aimed to elucidate the early dynamics of antiviral immunity and define the IFN-dependent mechanisms limiting viral spread during pulmonary infection with the murine hepatitis virus (MHV), a beta-coronavirus. While several innate immune cell types infiltrated the lungs concomitant with viral replication, the influx of type I IFN-responsive myeloid cells was essential for viral containment and prevention of fatal disease. Combining high-resolution transcriptomic analysis and genetic attenuation of interferon signaling, we delineated IFN-dependent cell-intrinsic and population-based transcriptional changes that determined viral replication and inflammatory maturation, respectively. While monocyte-derived macrophages exhibited the strongest pro-inflammatory transcriptional reprogramming during pulmonary infection, these maturation programs were impaired in the absence of IFN-signalling. Instead, IFN-deficient monocyte-derived macrophages expressed genes encoding for neutrophil attractants and IL1{beta}, resulting in enhanced lung injury. Our results reveal the requirement for type I IFN-induced antiviral states and inflammation-induced maturation programs to secure pulmonary viral containment.