Modulation of Acute Lung Injury by Type I Interferon Signaling

SUMMARY The proliferation of type 2 alveolar (AT2) cells is a critical step in the regeneration of the alveolar epithelium after acute lung injury, but the molecular pathways that regulate this process are unclear. Our preliminary findings strongly suggest that a specific host defense response, type I interferon (IFN-I) signaling, inhibits the proliferation of AT2 cells. We performed a high-throughput CRISPR screen, unexpectedly finding that despite its canonical antiviral properties, IFN-I signaling actually reduced the fitness of SARS-CoV-2- infected respiratory epithelial cells by restricting their proliferation after the initial peak of viral replication and cytopathic effect. We furthermore found that IFN-I signaling was not only necessary but sufficient for this antiproliferative response, and that it was also present in AT2 cells derived from induced pluripotent stem cells. Although IFN-I signaling has been implicated in driving lung pathology during SARS-CoV-2 infection in vivo, the underlying basis for this effect is unknown. Our in vitro data forms the foundation of our central hypothesis that IFN-I signaling promotes acute lung injury of diverse causes by inhibiting AT2 cellular proliferation during alveolar regeneration. In Aim 1, we will identify the molecular effectors that link IFN-I signaling activation to cell cycle arrest in respiratory epithelial cells. In Aim 2, we will determine whether inhibition of AT2 proliferation and alveolar regeneration is responsible for the pathogenic effect of IFN-I signaling in a mouse model of SARS- CoV-2 infection. In Aim 3, we will determine the potential of IFN-I signaling in AT2 cells to modulate alveolar regeneration after noninfectious acute lung injury. Together, these studies will clarify the fundamental biology of IFN-I signaling in the alveolar epithelium and facilitate our long-term objective of developing new disease- modifying treatments for acute lung injury and the acute respiratory distress syndrome.