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

Grabherr, S.; Waltenspuehl, A.; Luetge, M.; Buechler, L.; Cheng, H.-W.; Zielinska, K.; Caviezel-Firner, S.; Krebs, P.; Ludewig, B.; Pikor, N. B.

doi:10.1101/2022.02.01.478627

bioRxiv · 10.1101/2022.02.01.478627

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

Grabherr, S.·Waltenspuehl, A.·Luetge, M.·Buechler, L.·Cheng, H.-W.·Zielinska, K.·Caviezel-Firner, S.·Krebs, P.·Ludewig, B.·Pikor, N. B.

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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.

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Grabherr, S., Waltenspuehl, A., Luetge, M., Buechler, L., Cheng, H.-W., Zielinska, K., Caviezel-Firner, S., Krebs, P., Ludewig, B., Pikor, N. B.. 2022-02-01. TYPE I INTERFERON-DEPENDENT CELLULAR REMODELING DURING ACUTE PULMONARY MHV INFECTION. https://doi.org/10.1101/2022.02.01.478627

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