The SARS-CoV-2 S1 Spike Protein Promotes MAPK and NF-kB Activation in Human Lung Cells and Inflammatory Cytokine Production in Human Lung and Intestinal Epithelial Cells

Abstract

The coronavirus disease 2019 (COVID-19) pandemic began in January 2020 in Wuhan, China, with a new coronavirus designated SARS-CoV-2. The principal cause of death from COVID-19 disease quickly emerged as acute respiratory distress syndrome (ARDS). A key ARDS pathogenic mechanism is the “Cytokine Storm”, which is a dramatic increase in inflammatory cytokines in the blood. In the last two years of the pandemic, a new pathology has emerged in some COVID-19 survivors, in which a variety of long-term symptoms occur, a condition called post-acute sequelae of COVID-19 (PASC) or “Long COVID”. Therefore, there is an urgent need to better understand the mechanisms of the virus. The spike protein on the surface of the virus is composed of joined S1–S2 subunits. Upon S1 binding to the ACE2 receptor on human cells, the S1 subunit is cleaved and the S2 subunit mediates the entry of the virus. The S1 protein is then released into the blood, which might be one of the pivotal triggers for the initiation and/or perpetuation of the cytokine storm. In this study, we tested the hypothesis that the S1 spike protein is sufficient to activate inflammatory signaling and cytokine production, independent of the virus. Our data support a possible role for the S1 spike protein in the activation of inflammatory signaling and cytokine production in human lung and intestinal epithelial cells in culture. These data support a potential role for the SARS-CoV-2 S1 spike protein in COVID-19 pathogenesis and PASC.

Exploring the immunogenic properties of SARS-CoV-2 structural proteins: PAMP:TLR signaling in the mediation of the neuroinflammatory and neurologic sequelae of COVID-19

“…Most studies of SARS-CoV-2 structural proteins have been conducted in vitro using an array of human and mouse cells. Both the S protein or it’s S1 subunit is sufficient to elicit a proinflammatory immune response in primary cells and cell lines including human lung cells ( Forsyth et al, 2022 , Khan et al, 2021 , Patra et al, 2020 ), human endothelial cells ( Perico et al, 2022 ), human intestinal epithelial cells ( Forsyth et al, 2022 ), HL-60 cells ( Zhao et al, 2021 ), human monocytes/macrophages ( Karwaciak et al, 2021 , Khan et al, 2021 , Pantazi et al, 2021 , Schroeder and Bieneman, 2022 , Shirato and Kizaki, 2021 , Zhao et al, 2021 ), mouse macrophages ( Li et al, 2022 , Shirato and Kizaki, 2021 , Zhao et al, 2021 ), human peripheral blood mononuclear cells ( Olajide et al, 2021b ), and TF1PIGA null cells ( Yu et al, 2020 ). Interestingly, Zhao and colleagues examined the proinflammatory effects of different domains of the S protein and found that the N-terminal (NT) and receptor binding (RB) domains (D) failed to elicit a proinflammatory cytokine response.…”

Concern about the Effectiveness of mRNA Vaccination Technology and Its Long-Term Safety: Potential Interference on miRNA Machinery

“…S1 spike protein might be not only responsible for the adherence and the invasion of the virus to the host cells and the onset of the cytokine storm but also responsible for long-COVID syndrome [ 23 ]. Moreover, it was estimated that a greater number of free S1 spikes in the blood during COVID-19 infection is correlated with a poor prognosis of COVID-19 [ 24 ]. Fortunately, the huge number of the accumulated mutation in the spike protein of the latest variants of concern results in a disrupted recognition of certain Toll-like receptors (TLR), resulting in the lower activation of the NF-κB pathway and related signaling pathways [ 25 ].…”

The Novelty of mRNA Vaccines and Potential Harms: A Scoping Review

“…There is reason to believe that vaccines encoding the spike (S) protein of SARS-CoV-2 have additional mechanisms of harm, owing to the biological impacts of S protein specifically. There is a wide literature [150][151][152][153], and it is beyond the scope of this review to cover this in significant depth. However, the addition of spike protein adds another factor in assessing the complexity of RNA vaccines.…”