Association of pyroptosis and severeness of COVID-19 as revealed by integrated single-cell transcriptome data analysis

Cytokine storm and inflammatory cytokine release syndrome are often found to be associated with severe instances of the 2019 coronavirus disease (COVID-19). However, factors that contribute to the development of the COVID-19-associated cytokine storm and intensify the hyperinflammatory response are not well known. Here, we integratively analyzed scRNAseq data of 37,607 immune cells of eight different cell types from four studies involving COVID-19 patients in either moderate or severe conditions. Our analysis showed that pyroptosis—a lytic, inflammatory type of programmed cell death—may play a critical role in the SARS-CoV-2-induced cytokine storm. The expression of the key markers of pyroptosis, such as pro-inflammatory cytokine genes IL1B and IL18, is significantly higher in moderate and severe COVID-19 patients than in healthy controls. The pattern is more pronounced in macrophages and neutrophils than in adaptive immune cells such as T cells and B cells. Furthermore, the lack of interferon-gamma (IFN-γ) and overexpression of ninjurin 1 (NINJ1) in macrophages may exacerbate the systemic inflammation, as shown in severe COVID-19 patients. Finally, we developed a scoring metric to quantitatively assess single cell's pyroptotic state and demonstrated the use of this pyroptosis signature score to scRNAseq data. Taken together, our study underscores the importance of the pyroptosis pathway and highlights its clinical relevance, suggesting that pyroptosis is a cellular process that can be a potential target for the treatment of COVID-19 associated diseases.