Abstract
Cytokine storm is suggested as one of the major pathological characteristics of SARS-CoV-2 infection, although the mechanism for initiation of a hyper-inflammatory response, and multi-organ damage from viral infection is poorly understood. In this virus-cell interaction study, we observed that SARS-CoV-2 infection or viral spike protein expression alone inhibited angiotensin converting enzyme-2 (ACE2) receptor protein expression. The spike protein promoted an angiotensin II type 1 receptor (AT1) mediated signaling cascade, induced the transcriptional regulatory molecules NF-κB and AP-1/c-Fos via MAPK activation, and increased IL-6 release. SARS-CoV-2 infected patient sera contained elevated levels of IL-6 and soluble IL-6R. Up-regulated AT1 receptor signaling also influenced the release of extracellular soluble IL-6R by the induction of the ADAM-17 protease. Use of the AT1 receptor antagonist, Candesartan cilexetil, resulted in down-regulation of IL-6/soluble IL-6R release in spike expressing cells. Phosphorylation of STAT3 at the Tyr705 residue plays an important role as a transcriptional inducer for SOCS3 and MCP-1 expression. Further study indicated that inhibition of STAT3 Tyr705 phosphorylation in SARS-CoV-2 infected and viral spike protein expressing epithelial cells did not induce SOCS3 and MCP-1 expression. Introduction of culture supernatant from SARS-CoV-2 spike expressing cells on a model human liver endothelial Cell line (TMNK-1), where transmembrane IL-6R is poorly expressed, resulted in the induction of STAT3 Tyr705 phosphorylation as well as MCP-1 expression. In conclusion, our results indicated that the presence of SARS-CoV-2 spike protein in epithelial cells promotes IL-6 trans-signaling by activation of the AT1 axis to initiate coordination of a hyper-inflammatory response.
Highlights
The novel human coronavirus causative agent of coronavirus disease-19 (COVID-19) initiates and promotes rapid disease spread and severity
We observed that SARS-CoV-2 infection or spike protein expression in human epithelial cells inhibits angiotensin converting enzyme-2 (ACE2) expression leading to the induction of angiotensin II type 1 receptor (AT1) signaling, and promotion of IL-6/soluble IL-6R release
We propose that SARS-CoV-2 infection in pulmonary epithelial cells induces IL-6 trans-signaling for secretion of chemokines; like monocyte chemoattractant protein-1 (MCP-1), from pulmonary vascular endothelial cells to attract monocytes/macrophages and create a hyperinflammatory state leading to enhanced disease severity and acute respiratory distress syndrome
Summary
The novel human coronavirus causative agent of coronavirus disease-19 (COVID-19) initiates and promotes rapid disease spread and severity. Potential mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease progression include a high rate of viral replication, resulting in enhanced host cell cytolysis, as well as, production of inflammatory cytokines and chemokines that perpetuate damage [1]. Our current understanding links COVID-19 with the development of a maladaptive immune response where multi-organ dysfunction may coincide with a severe disease state. The pathological mechanisms involved in multi-organ damage caused by SARS-CoV-2 infection are not well understood. Widespread distribution of macrophages throughout organs or systemic virus infection may be contributing factors for underlying multi-organ dysfunction due to macrophage activation and infiltration occurring in the lungs of COVID-19 patients, who are known to secrete high levels of inflammatory cytokines [2]
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