Preprint: COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis, 2021, Sinha et al

Abstract

A 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.

Open access, https://www.biorxiv.org/content/10.1101/2021.11.28.470269v2

 

My bolding.

"Consistent with the fact that PCLD occurs in survivors of severe disease 165 that required hospitalization(39), we found that sViP signature was induced significantly higher in hospitalized 166 compared to non-hospitalized subjects (Figure 2H). Finally, we asked what, if any relationship exists between 167 another poorly understood feature of long-haul COVID-19, i.e., severe fatigue(40, 41). To improve rigor, we 168 analyzed a set of other well-defined fatigue syndromes (e.g., gulf war illness, chronic fatigue syndrome, and 169 idiopathic chronic fatigue) and for consistency, restricted the analysis to only whole blood/PBMC samples 170 (Figure 2I). ViP/sViP and CoV-lung immune signatures were induced only in CoV samples, but not in the remaining fatigue-associated syndromes (Figure 2I), indicating that gene expression signatures in long-haul 172 COVID-19 are distinct from other fatigue-associated syndromes. Instead, fatigue in long-haul COVID-19 may be 173 of similar reasons/pathophysiology that has been observed in IPF (42). It is noteworthy that profound fatigue is a 174 shared phenomenon in both IPF and sarcoidosis(42, 43), both carry the risk of progressive fibrosis, and both 175 conditions induce the ViP/sViP response (Figure 2A). 176

Taken together, these results show that when it comes to gene expression patterns, long-haul PCLD is 177 closest to IPF: both are characterized by profound fatigue, diffuse and progressive lung fibrosis, and share gene 178 expression patterns. The latter suggests that these two diseases may also share molecular and cellular mechanisms 179 of disease pathogenesis."