SARS-CoV-2 early infection signature identified potential key infection mechanisms and drug targets

Abstract

Background The ongoing COVID-19 outbreak has caused devastating mortality and posed a significant threat to public health worldwide. Despite the severity of this illness and 2.3 million worldwide deaths, the disease mechanism is mostly unknown. Previous studies that characterized differential gene expression due to SARS-CoV-2 infection lacked robust validation. Although vaccines are now available, effective treatment options are still out of reach. Results To characterize the transcriptional activity of SARS-CoV-2 infection, a gene signature consisting of 25 genes was generated using a publicly available RNA-Sequencing (RNA-Seq) dataset of cultured cells infected with SARS-CoV-2. The signature estimated infection level accurately in bronchoalveolar lavage fluid (BALF) cells and peripheral blood mononuclear cells (PBMCs) from healthy and infected patients (mean 0.001 vs. 0.958; P < 0.0001). These signature genes were investigated in their ability to distinguish the severity of SARS-CoV-2 infection in a single-cell RNA-Sequencing dataset. TNFAIP3, PPP1R15A, NFKBIA, and IFIT2 had shown bimodal gene expression in various immune cells from severely infected patients compared to healthy or moderate infection cases. Finally, this signature was assessed using the publicly available ConnectivityMap database to identify potential disease mechanisms and drug repurposing candidates. Pharmacological classes of tricyclic antidepressants, SRC-inhibitors, HDAC inhibitors, MEK inhibitors, and drugs such as atorvastatin, ibuprofen, and ketoconazole showed strong negative associations (connectivity score < − 90), highlighting the need for further evaluation of these candidates for their efficacy in treating SARS-CoV-2 infection. Conclusions Thus, using the 25-gene SARS-CoV-2 infection signature, the SARS-CoV-2 infection status was captured in BALF cells, PBMCs and postmortem lung biopsies. In addition, candidate SARS-CoV-2 therapies with known safety profiles were identified. The signature genes could potentially also be used to characterize the COVID-19 disease severity in patients’ expression profiles of BALF cells.

Severe COVID-19 Shares a Common Neutrophil Activation Signature with Other Acute Inflammatory States

“…Our work expands the efforts of others [ 23 , 109 , 110 , 111 , 112 ] and of our group [ 21 ] to identify networks and pathways involved in the pathogenesis of severe COVID-19. In accordance with our findings, it has recently been demonstrated that neutrophils accumulate in inflamed tissues of COVID-19 patients as a consequence of T-cell driven pro-inflammatory cytokine and chemokine release, which do not return to a homeostatic level due to an ineffective T cell cytotoxic response [ 101 , 102 ].…”

Delineating COVID-19 immunological features using single-cell RNA sequencing

“…Furthermore, there are many other studies using scRNA-seq from COVID-19 patients to conduct therapeutic drug development or validation. 81,83,84 Many studies explored the post-COVID-19 symptoms by cytokine storm on diverse organs by using scRNA-seq and other omics data. 2,85 Mutual corroboration of results in transcriptomics and other omics substantially improves the reliability of new findings, which has been more recognized in the current COVID-19 research.…”

Severe COVID-19 shares a common neutrophil activation signature with other acute inflammatory states

“…Our work expands the efforts of others [87][88][89][90][91] and our group 92 to identify networks and pathways involved in the pathogenesis of severe COVID-19. Our multi-layered transcriptomics approach is in agreement with the computational model developed by Ding et al 18 , which is based on a network-informed analysis of the interaction of SARS-CoV-2 and HLH related genes.…”

“…Our work expands the efforts of others [110][111][112][113][114] and our group [21] to identify networks and pathways involved in the pathogenesis of severe COVID-19. In accordance with our findings, it has recently been demonstrated that neutrophils accumulate in inflamed tissues of COVID-19 patients as a consequence of T-cell driven pro-inflammatory cytokine and chemokine release, which does not return to a homeostatic level due to an ineffective T cell cytotoxic response [102,103].…”