SARS-CoV-2 Spike Protein and Long COVID-Part 2: Understanding the Impact of Spike Protein and Cellular Receptor Interactions on the Pathophysiology of Long COVID Syndrome

Abstract

SARS-CoV-2 infection has had a significant impact on global health through both acute illness, referred to as coronavirus disease 2019 (COVID-19), and chronic conditions (long COVID or post-acute sequelae of COVID-19, PASC). Despite substantial advancements in preventing severe COVID-19 cases through vaccination, the rise in the prevalence of long COVID syndrome and a notable degree of genomic mutation, primarily in the S protein, underscores the necessity for a deeper understanding of the underlying pathophysiological mechanisms related to the S protein of SARS-CoV-2. In this review, the latest part of this series, we investigate the potential pathophysiological molecular mechanisms triggered by the interaction between the spike protein and cellular receptors. Therefore, this review aims to provide a differential and focused view on the mechanisms potentially activated by the binding of the spike protein to canonical and non-canonical receptors for SARS-CoV-2, together with their possible interactions and effects on the pathogenesis of long COVID.

Keywords: cellular receptors; interactions; spike protein.

Figure 1

Schematic representation of SARS-CoV-2 infection pathways, spike protein domains, and main receptors. The SARS-CoV-2 spike (S) glycoprotein consists of two non-covalently linked subunits (S1 and S2). The S1 subunit first mediates virus binding to host cell receptors, primarily binding to ACE2 through its receptor-binding domain (RBD). However, other molecules, such as NRP1, TLR2/4, CD147, DPP4, nAchR, and TfR, can also act as receptors or co-receptors, depending on the cell type. Cell entry can occur via two pathways, depending on the expression of metalloproteinases on the cell surface. (A) In the absence or low expression of TMPRSS2/ADAM17, the virus enters the cell through clathrin-mediated endocytosis. Subsequently, the S2 subunit is cleaved by endosomal proteases (such as cathepsin L) or ADAM17 in early endosomes, and viral-cell membrane fusion occurs within late endosomes, leading to the release of viral RNA. (B) In the presence of adequate levels of metalloproteinases, the S2 subunit is cleaved at the S2′ site at the cell membrane after conformational changes following the interaction of S1 with ACE2 or alternative receptors, leading to viral envelope-cell membrane fusion. Abbreviations: ACE2: Angiotensin-converting enzyme 2; TMPRSS2: Type II transmembrane serine protease; ADAM17: A disintegrin and metalloprotease 17; NRP1: Neuropilin-1; TLR2/4: Toll-like receptors 2 and 4; AXL: Tyrosine-protein kinase receptor; nAchR: Nicotinic acetylcholine receptor; DPP4: Dipeptidyl peptidase 4; TfR: Transferrin receptor. Created in BioRender. de Melo, M.P. (2025) https://BioRender.com.

Figure 2

Schematic overview of the molecular mechanisms triggered by the interplay between SARS-CoV-2 S protein, ACE2, and integrin β1 receptors. Binding of the SARS-CoV-2 S protein to ACE2 or integrin β1 receptors can disrupt the balance of the renin–angiotensin system (RAS) and activate the Ang II/AT1R axis. Activation of AT1R and viral infection itself can initiate several intracellular signaling pathways, including Ca²⁺ influx, activation of TMEM16F scramblase, and externalization of phosphatidylserine (PtdSer) to the outer cell membrane, ultimately leading to ADAM17 activation. The sheddase activity of ADAM17, in combination with AT1R-induced RAGE activation, may significantly contribute to the inflammatory process by activating inflammatory factors such as Notch and NF-kB proteins, which, in turn, promote the production of pro-inflammatory cytokines like TNF-α, IL-6, R-IL6, and IL-1β. Created in BioRender. de Melo, M.P. (2025) https://BioRender.com.

Figure 3

Schematic overview of the molecular mechanisms triggered by the interplay between SARS-CoV-2 S protein and TLR2/4 receptors. The SARS-CoV-2 S protein activates TLR2/4 (in red) and PANX1/P2X7, which, in turn, promote the activation of NF-κB, the NLRP3 inflammasome, and ADAM17. These mechanisms collectively lead to the production of pro-inflammatory cytokines such as TNF-α, IL-6, RIL-6, IL-1β, and IL-18, contributing to the cytokine storm and enhancing viral infection. Created in BioRender. de Melo, M.P. (2025) https://BioRender.com.

Figure 4

Schematic overview of the molecular mechanisms involving the interaction between the SARS-CoV-2 S protein and NRP1, DPP4, and CD147 cellular receptors. NRP1 (in red) can function as either a co-receptor or a receptor, depending on the tissue or cell type. DPP4 (in red) may facilitate the S protein binding to ACE2 (in red), and CD147 (in red) can eventually act as a receptor. Additionally, both DPP4 and CD147 (in red) can promote the production of pro-inflammatory cytokines, VEGF, and the activation of NRP1. The interaction between VEGF, VEGF-R2, and NRP1 can stimulate angiogenesis and cell migration. Moreover, elevated VEGF levels can activate ADAM9/10 metalloproteinases, which leads to the release of both the extracellular domain and the cytoplasmic tail of NRP1, thereby disrupting the VEGF-NRP1 signaling pathway. Created in BioRender. de Melo, M.P. (2025) https://BioRender.com.