Role of Xenosialylation in Post-Infectious and Post-Vaccination Complications, Including Covid-19 and Anti-SARS-CoV-2 Vaccination.

The host glycosylation mechanism, with sialic acids as a key component, is essential for synthesizing carbohydrate components in viral glycoproteins. We hypothesize a correlation between the presence of the Neu5Gc on the host tissue and the development of infectious complications, adverse vaccine reactions, and autoimmune diseases. In certain mammals, including humans, the loss of the Cytidine Monophospho-N-Acetylneuraminic Acid Hydroxylase gene (negative-CMAH) prevents the synthesis of Neu5Gc, which acts as a Mammalian-associated Carbohydrate Antigen (MCA), (XeSiAs-Neu5Gc). When negative-CMAH species consume products from positive-CMAH mammals or are exposed to non-human cell-derived medicines, Neu5Gc can be integrated into their glycocalyx through a process called xenosialylation, eliciting an inflammatory response (xenosialitis) and prompting the production of circulating anti-Neu5Gc antibodies aimed at eliminating Neu5Gc. We hypothesize that in the case of xenosialylation, neutralizing antiviral antibodies from infections or vaccinations-including those for SARS-CoV-2-may cross-react with the XeSiAs-Neu5Gc glycans, as these resemble viral envelope antigens produced by the host's glycosylation. Additionally, circulating anti-Neu5Gc antibodies may also react with other circulating antibodies, including newly formed antiviral ones with a XeSiAs-Neu5Gc-contaminated Fc region. This can lead to the serum removal of the anti-inflammatory antibodies, leaving only hyperinflammatory IgG agalactosylated antibodies. Such conditions are also seen in various inflammatory and autoimmune diseases. We hypothesize that the combination of antibody cross-reaction and the removal of the XeSiAs-Neu5Gc-contaminated Fc region anti-inflammatory antibodies may intensify severe inflammatory responses like cytokine storms and coagulopathies in COVID-19 patients and those vaccinated. Assessing serum levels of total XeSiAs-Neu5Gc antibodies could be a valuable method for identifying patients at risk of severe complications from viral infections and vaccinations, including SARS-CoV-2. This strategy may also deepen our understanding of the pathogenesis of autoimmune diseases linked to post-infectious and post-vaccination complications, particularly for viruses utilizing the host glycosylation machinery, such as SARS-CoV-2, IAV, EBV, and others.