These series of molecular events are unlikely for any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related antigen in the absence of severe coronavirus disease 2019 (COVID-19), where SARS-CoV-2 is contained in the respiratory system. (A,B) Parallel to immune system activation, circulating S protein/subunits/peptide fragments (B) binding to ACE2 may occur not only to ACE2-expressing endothelial cells, but also in multiple cell types of the vasculature and surrounding tissues due to antigen diffusion (e.g., in fenestrated or discontinuous capillary beds) (A, red arrows). Also shown are dendritic cells (professional antigen-presenting cells, APCs) engulfing circulating antigens, and antibody-mediated binding of B cells to cell-anchored antigens. Further research will clarify the impact of the S1/S2 subunits stabilizing D614G (or other) mutation or of a mutated furin cleavage site in antigen distribution, the immunogenicity of the vaccine, and induced adverse events (AEs). The Pfizer–BioNTech and Moderna constructs do not contain a mutated S1/S2 furin cleavage site. The events shown will occur in the apical and/or basolateral surfaces of polarized (e.g., epithelial) cells. Antigen sorting and trafficking may also induce the release of S protein-containing exosomes. Furin-mediated proteolytic cleavage (as in SARS-CoV-2-infected cells) in the absence of a mutated S1/S2 furin cleavage site at the TGN may result in shedding of cleaved S1 and conversion of S2 into its postfusion structure (S2*). Although the extent of antigen expression per cell remains unknown, it is reasonable to assume that this process results in rather extended decoration of transfected cells with S protein. After sorting in the trans Golgi network (TGN), S protein acquires its final position in the transfected human cell membrane, where S1 is exposed to the extracellular space (i.e., may face circulation). Following LNP internalization and mRNA release, the authentic viral signal peptide (as in the Pfizer–BioNTech and Moderna vaccines) drives antigen production in the lumen of the endoplasmic reticulum (ER) where it adopts its natural transmembrane localization via subunit 2 (S2) anchoring.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |