[PMC free article] [PubMed] [Google Scholar] 58

[PMC free article] [PubMed] [Google Scholar] 58. protein related to immune activation and function via the toll-like receptors (TLRs), B cells, and T cells. We aim to provide a comprehensive analysis of immune (S)-3,5-DHPG epitopes of Spike protein, thereby contributing to the development of new strategies for broad neutralization or universal vaccination. Keywords: Broad Neutralization, COVID-19, Genetic Entropy, Glycosylation, Immune Epitope, Spike, Universal Vaccine Introduction SARS-CoV-2, the etiological pathogen of COVID-19, is currently responsible for over 760 million cases of illness and 6. 9 million deaths as of July 2023 1. As a single-stranded positive-sense betacoronavirus, SARS-CoV-2 exploits the host machinery for replication 2. Spike protein is a key envelope glycoprotein for SARS-CoV-2 infection. The SARS-CoV-2 Spike protein assembles into (S)-3,5-DHPG trimers that can be broadly split into two subunits, S1 and S2, divided by a furin cleavage site (Figure 1A & B). The S1 subunit is primarily responsible for initial angiotensin-converting enzyme 2 (ACE2) interaction and binding, while the S2 subunit enables membrane fusion 3. The S1 subunit contains a receptor-binding site (RBD), which directly binds to ACE2, as well as an N-terminal domain (NTD), which is considered primarily structural in Spike function 4. In contrast, the S2 domain contains two heptad repeat regions (HR1 and HR2) as well as a fusion peptide domain (FP) 5. The FP acts immediately after the RBD-mediated Spike-ACE2 interaction by inserting itself into the host membrane, causing a drastic conformational change that brings the HR1 and HR2 domains into proximity with the cell membrane, leading to membrane fusion and viral internalization 6. Open in a separate window Figure 1: Schematics of Spike structure and SARS-CoV-2 infection(A) Structure of the SARS-CoV-2 Spike protein (PDB ID 6VXX). (B) Diagram of SARS-CoV-2 Spike (S) gene. NTD: N-terminal domain; RBD: receptor-binding domain; FP: fusion peptide; HR1: heptad repeat 1; HR2: heptad repeat 2; TM: transmembrane region; IC: intracellular domain. (C) The primary mechanism of SARS-CoV-2 cell entry and propagation. Spike protein recognizes and binds to targeted host receptors, predominantly ACE2 receptor 3,7, initiating viral entry into host cells via endocytosis. After entry, the viral RNA escapes the host endosome and exploits the translational machinery of the cell for viral protein production 8, followed by assembly and release of the virions from the host cells 9,10 (Figure 1B). Since it relies on the translational mechanisms of host cells, Spike protein is subject to post-translational modifications (PTMs), which may alter Spike-mediated host-virus interactions SLC2A2 and host immune responses. Particularly, glycosylation, the addition of glycan molecules to a protein, has been demonstrated to affect the interaction of a variety of biomolecules with Spike protein 11. Since the identification of its role in the initiation of SARS-CoV-2 infection, Spike protein has been of interest to the scientific community as a primary target for vaccine design and therapeutics 5,12C14. The Spike-based vaccine-elicited host immune cell responses can be broadly divided into three arms: innate immune response, in part as a result of toll-like receptor (TLRs) (S)-3,5-DHPG recognition; T cell response; and B cell response 15C20. In brief, innate receptor ligands such as TLR ligands in the vaccine can activate innate immune cells, particularly antigen-presenting cells (APCs), which further prime the activation of CD4+ and CD8+ T cells. Among the activated CD4+ T cells, follicular helper T (Tfh) cells contribute to B cell activation, plasma cell maturation, and antibody production, while type 1 helper T (Th1) cells help potentiate APC function, CD8+ T cell activation, and cytotoxicity. The vaccine-elicited antibodies provide protection through the neutralization of viruses, while the cytotoxic T lymphocytes (CTLs) eliminate infected host cells to promote clearance of infections (Figure 2). The immune subset specialization is heavily influenced by the vaccine adjuvants, while the specificity of the vaccine-elicited antibodies and CTLs is largely defined by the antigenic immune epitopes of the vaccine 21,22. Open in a separate window Figure 2: A general overview of host immune responses to Spike-based vaccinesUpon host exposure to Spike-based vaccines, antigen-presenting cells (APCs) sample, process, and present the antigens to CD4+ and CD8+ T cells via MHCII and MHCI respectively. Activated CD4+ T cells can differentiate into follicular helper T (Tfh) and type 1 T helper (Th1) cells which further mediate B cell activation and plasma cell maturation. Th1 cells also aid in priming APC activation and maturation to enhance antigen presentation. Activated CD8+ T cells also receive assistance from Th1 cells to potentiate development.