RNA Sequencing data suggests that COVID-19 patients’ deaths may be due to uncontrolled host inflammatory processes rather than an active viral infection

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection.

Researchers from Harvard Medical School show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated the transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.

Transcriptional profiling reveals enrichment of neutrophil and lung fibrosis gene pathways

(A) Volcano plot (P value vs. fold change) comparing gene expression in cases vs. controls. Up- (orange) and down-regulated genes (cyan) are highlighted, and immune-related genes that are differentially expressed are named. The horizontal dashed line represents an adjusted P value of 0.05 (Wald test in DESeq2, multiple test correction by Benjamini–Hochberg [BH]), and the vertical dashed lines represent log2FC of −1 and 1. (B) GO network analysis of the top 60 enriched GO terms in the up-regulated genes (Fisher’s exact test using enrichGO function in R package clusterProfiler, multiple test correction by BH). (C) Heatmap of the up-regulated DEGs (Wald test in DESeq2, multiple test correction by BH) involved in the GO network module neutrophil-mediated immunity. (D) Immunofluorescence microscopy of lung section stained with DAPI (blue) and antibodies against myeloperoxidase (green) and neutrophil elastase (red). Areas of NETosis are highlighted with arrows. (E) Heatmap of the up-regulated DEGs (Wald test, multiple test correction by BH) involved in the GO network module extracellular structure organization.

Wu M, Chen Y, Xia H, Wang C, Tan CY, Cai X, Liu Y, Ji F, Xiong P, Liu R, Guan Y, Duan Y, Kuang D, Xu S, Cai H, Xia Q, Yang D, Wang MW, Chiu IM, Cheng C, Ahern PP, Liu L, Wang G, Surana NK, Xia T, Kasper DL. (2020) Transcriptional and proteomic insights into the host response in fatal COVID-19 cases. PNAS [Epub ahead of print]. [article]

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