Transcriptome Heterogeneity in COVID-19-induced Acute Respiratory Distress Syndrome

Abstract

Abstract COVID-19 is a major etiology of acute respiratory distress syndrome (ARDS). The biological phenotypes and underlying mechanisms in COVID-19-induced ARDS are not fully understood. Bronchoalveolar lavage fluid (BALF) cells and clinical data were collected from patients with COVID-19-induced ARDS. Principal component analysis of genome-wide expression data obtained from bulk RNA sequencing of BALF cells subgrouped COVID-19-induced ARDS patients. Moreover, comparing transcriptome profiles between the subgroups showed two biological phenotypes, illustrated by up- and down-regulation of interferon (IFN) responses, despite no significant differences in clinical characteristics including onset and outcomes. In the low-IFN phenotype, in contrast to the high-IFN phenotype, the TLR-MyD88-IFN regulatory factor (IRF) 5 and cGAS-STING1 axes related to type Ⅰ IFN and the IRF8-interleukin (IL)-12-STAT4 and IRF1-IL-15-DNAX-activation protein 10 axes related to type Ⅱ IFN were inactivated at the transcriptional level, together with the PERK-C/EBP homologous protein axis and the IL-10-hemoglobin scavenger receptor CD163 axis. The pathogenesis of ARDS in the low-IFN phenotype was illustrated by damage to type II alveolar epithelial cells due to increased viral replication by reduced antiviral response, cytotoxicity, and apoptotic signaling and impaired free hemoglobin catabolism. Our data uncovered heterogeneous IFN responses, the underlying mechanisms, and related pathogenesis in COVID-19-induced ARDS.