SARS-CoV-2 Spike protein promotes hyper-inflammatory response that can be ameliorated by Spike-antagonistic peptide and FDA-approved ER stress and MAP kinase inhibitorsin vitro

Abstract

SARS-CoV-2 infection causes an inflammatory cytokine storm and acute lung injury. Currently there are no effective antiviral and/or anti-inflammatory therapies. Here we demonstrate that 2019 SARS-CoV-2 spike protein subunit 1 (CoV2-S1) induces high levels of NF-κB activations, production of pro-inflammatory cytokines and mild epithelial damage, in human bronchial epithelial cells. CoV2-S1-induced NF-κB activation requires S1 interaction with human ACE2 receptor and early activation of endoplasmic reticulum (ER) stress, and associated unfolded protein response (UPR), and MAP kinase signalling pathways. We developed an antagonistic peptide that inhibits S1-ACE2 interaction and CoV2-S1-induced productions of pro-inflammatory cytokines. The existing FDA-approved ER stress inhibitor, 4-phenylburic acid (4-PBA), and MAP kinase inhibitors, trametinib and ulixertinib, ameliorated CoV2-S1-induced inflammation and epithelial damage. These novel data highlight the potentials of peptide-based antivirals for novel ACE2-utilising CoVs, while repurposing existing drugs may be used as treatments to dampen elevated inflammation and lung injury mediated by SARS-CoV-2.

NF-κB Pathway as a Potential Target for Treatment of Critical Stage COVID-19 Patients

“…Key examples were TNF, NF-κB, IL-1, and ALOX5 signaling pathways ( 17 ). Several recent reports have demonstrated the NF-κB pathway as the central signaling pathway for the SARS-CoV-2 infection-induced pro-inflammatory cytokine/chemokine response ( 16 – 18 , 35 – 37 ). Huang et al.…”

“…CoV2-S1-induced NF-κB activation required S1 interaction with human ACE2 receptor and early activation of endoplasmic reticulum (ER) stress, associated unfolded protein response (UPR), and MAP kinase signaling pathways. Notably, a higher activity in NF-κB activation of CoV-2-S1 compared to CoV-S1 was found, probably correlating with the higher binding affinity of CoV-2-S1 to ACE2 receptor ( 37 ). Sohn et al.…”

“…CoV2-S1-induced NF-kB activation required S1 interaction with human ACE2 receptor and early activation of endoplasmic reticulum (ER) stress, associated unfolded protein response (UPR), and MAP kinase signaling pathways. Notably, a higher activity in NF-kB activation of CoV-2-S1 compared to CoV-S1 was found, probably correlating with the higher binding affinity of CoV-2-S1 to ACE2 receptor (37). Sohn et al showed that C-C motif (CC) chemokines [CC chemokine ligand (CCL) 2, CCL7, CCL8, CCL24, CCL20, CCL13, and CCL3], C-X-C motif (CXC) chemokines [CXC chemokine ligand (CXCL) 2 and CXCL10], and chemokine receptor subfamilies, as well as IL-1b and its downstream inflammatory signaling molecules (IL1R1, MYD88, IRAK1, TRAF6, NFKBIA, NFKB1, RELA) were dramatically elevated in peripheral blood mononuclear cells (PBMC) from COVID-19 patients compared to healthy controls.…”

“…Key examples were TNF, NF-kB, IL-1, and ALOX5 signaling pathways (17). Several recent reports have demonstrated the NF-kB pathway as the central signaling pathway for the SARS-CoV-2 infection-induced proinflammatory cytokine/chemokine response (16)(17)(18)(35)(36)(37). Huang et al showed in a human in vitro model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2 a rapid transcriptomic change in infected cells, characterized by a shift to an inflammatory phenotype with upregulation of NF-kB signaling and NF-kB target genes by day 1 post-infection, followed by a loss of the mature alveolar program (16).…”

Dysregulation of Cell Signaling by SARS-CoV-2

“…A preprint by Hsu et al . suggests that the SARS-CoV-2 S protein contributes to host hyperinflammatory responses via its binding to the ACE2 receptor [ 23 ]. This interaction stimulates the MAPK–NF-ĸB axis and results in the release of proinflammatory cytokines such as TNF-α and CCL2.…”