COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis

Abstract

ABSTRACTA long-haul form of progressive fibrotic lung disease has emerged in the aftermath of this pandemic, i.e., post-COVID-19 lung disease (PCLD), for which we currently lack insights into pathogenesis, disease models, or treatment options. Using a combination of rigorous AI-guided computation and experiments, we show that COVID-19 resembles idiopathic pulmonary fibrosis (IPF) at a fundamental level; they share prognostic signatures in the circulating monocytes and the lung [Viral pandemic (ViP) and IPF signatures], an IL15-centric cytokine storm and the pathognomonic AT2 cytopathic changes, e.g., DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP). These changes were induced in SARS-CoV-2-challenged adult lung organoids and hamsters and reversed with effective anti-CoV-2 therapeutics in the hamsters. Mechanistically, using protein-protein interaction (PPI)-network approaches, we pinpointed ER stress as an early shared trigger for both COVID-19 and IPF. We validated the same in the lungs of deceased subjects with COVID-19 and SARS-CoV-2-challenged hamster lungs by immunohistochemistry. We confirmed that lungs from tg-mice, in which ER stress is induced specifically in the AT2 cells, faithfully recapitulate the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2. Thus, like IPF, COVID-19 may be driven by injury-induced ER stress that culminates into progenitor state arrest and SASP in AT2 cells. The ViP gene signatures in monocytes may help prognosticate those at highest risk of fibrosis. The insights, signatures, disease models identified here are likely to spur the development of therapies for patients with IPF and other fibrotic interstitial lung disease.One Sentence SummarySevere COVID-19 triggers cellular processes seen in fibrosing Interstitial Lung Disease