Abstract
As one of the current global health conundrums, COVID-19 pandemic caused a dramatic increase of cases exceeding 79 million and 1.7 million deaths worldwide. Severe presentation of COVID-19 is characterized by cytokine storm and chronic inflammation resulting in multi-organ dysfunction. Currently, it is unclear whether extrapulmonary tissues contribute to the cytokine storm mediated-disease exacerbation. In this study, we applied systems immunology analysis to investigate the immunomodulatory effects of SARS-CoV-2 infection in lung, liver, kidney, and heart tissues and the potential contribution of these tissues to cytokines production. Notably, genes associated with neutrophil-mediated immune response (e.g. CXCL1) were particularly upregulated in lung, whereas genes associated with eosinophil-mediated immune response (e.g. CCL11) were particularly upregulated in heart tissue. In contrast, immune responses mediated by monocytes, dendritic cells, T-cells and B-cells were almost similarly dysregulated in all tissue types. Focused analysis of 14 cytokines classically upregulated in COVID-19 patients revealed that only some of these cytokines are dysregulated in lung tissue, whereas the other cytokines are upregulated in extrapulmonary tissues (e.g. IL6 and IL2RA). Investigations of potential mechanisms by which SARS-CoV-2 modulates the immune response and cytokine production revealed a marked dysregulation of NF-κB signaling particularly CBM complex and the NF-κB inhibitor BCL3. Moreover, overexpression of mucin family genes (e.g. MUC3A, MUC4, MUC5B, MUC16, and MUC17) and HSP90AB1 suggest that the exacerbated inflammation activated pulmonary and extrapulmonary tissues remodeling. In addition, we identified multiple sets of immune response associated genes upregulated in a tissue-specific manner (DCLRE1C, CHI3L1, and PARP14 in lung; APOA4, NFASC, WIPF3, and CD34 in liver; LILRA5, ISG20, S100A12, and HLX in kidney; and ASS1 and PTPN1 in heart). Altogether, these findings suggest that the cytokines storm triggered by SARS-CoV-2 infection is potentially the result of dysregulated cytokine production by inflamed pulmonary and extrapulmonary (e.g. liver, kidney, and heart) tissues.
Highlights
The outbreak of Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to more than 79 million cases and 1.7 million deaths worldwide to date, as reported by the World Health Organization
The analysis revealed the downregulation of 3928 genes in lung tissue, 3881 genes in liver tissue, 4848 genes in kidney tissue, and 3312 genes in heart tissue. 1375 genes out of these genes were commonly downregulated across the four types of tissues (Figure S1D)
Examination of the enrichment of differentially expressed immune response genes in SARS-CoV-2 infected lung, liver, kidney, and heart tissues was carried out using the immune response gene ontology set (GO:0006955) from AmiGO 2 database as a reference
Summary
The outbreak of Coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), led to more than 79 million cases and 1.7 million deaths worldwide to date, as reported by the World Health Organization. Analysis of pulmonary and extrapulmonary tissue biopsy/autopsy samples revealed interstitial infiltration of lymphocytes, macrophages, neutrophils, NK cells and dendritic cells into lung tissue [8, 9]; lymphocytes into liver tissue [10]; lymphocytes and macrophages into kidney tissue [11]; and mononuclear inflammatory cells into heart tissue [8] These immune cells are initially attracted to counteract SARS-CoV-2 infection, the exacerbation of the immune response elicited by the overexpressed cytokines and transcriptional shifts can potentially promote tissue remodeling, cellular apoptosis and tissue dysfunction and cytotoxicity [11]. The progression of systemic inflammation and cytokine storm (e.g. significantly increased IL-2, IL-7, IL-10, GSCF, IP10, MCP-1, MIP1A and TNF-a levels) can potentially lead to multiorgan dysfunction (observed in approximately 5% of COVID-19 patients) and viral sepsis increasing the risk of mortality [12, 13]
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