Why Blood Group A Individuals Are at Risk Whereas Blood Group O Individuals Might Be Protected from SARS-CoV-2 (COVID-19) Infection: A Hypothesis Regarding How the Virus Invades the Human Body via Abo(H) Blood Group-Determining Carbohydrates

Abstract

While the angiotensin converting enzyme 2 (ACE2) protein is defined as the primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, the viral serine molecule might be mobilized by the host's transmembrane protease serine subtype 2 (TMPRSS2) enzyme from the viral spike (S) protein and hijack the host’s N-acetyl-D-galactosamine (GalNAc) metabolism. The resulting hybrid, serologically A-like/Tn (T-nouvelle) structure potentially acts as a host–pathogen functional molecular bridge. In humans, this intermediate structure will hypothetically be replaced by ABO(H) blood group-specific, mucin-type structures, in the case of infection hybrid epitopes, implicating the phenotypically glycosidic accommodation of plasma proteins. The virus may, by mimicking the synthetic pathways of the ABO(H) blood groups, bind to the cell surfaces of the blood group O(H) by formation of a hybrid H-type antigen as the potential precursor of hybrid non-O blood groups, which does not affect the highly anti-glycan aggressive anti-A and anti-B isoagglutinin activities, exerted by the germline-encoded nonimmune immunoglobulin M (IgM). In the non-O blood groups, which have developed from the H-type antigen, these IgM activities are downregulated by phenotypic glycosylation, while adaptive immunoglobulins might arise in response to the hybrid A and B blood group structures, bonds between autologous carbohydrates and foreign peptides, suggesting the exertion of autoreactivity. The non-O blood groups thus become a preferred target for the virus, whereas blood group O(H) individuals, lacking the A/B phenotype-determining enzymes and binding the virus alone by hybrid H-type antigen formation, have the least molecular contact with the virus and maintain the critical anti-A and anti-B isoagglutinin activities, exerted by the ancestral IgM, which is considered the humoral spearhead of innate immunity.

A longitudinal study of convalescent plasma (CCP) donors and correlation of ABO group, initial neutralizing antibodies (nAb), and body mass index (BMI) with nAb and anti‐nucleocapsid (NP) SARS‐CoV‐2 antibody kinetics: Proposals for better quality of CCP collections

“…Arend 60 recently proposed a different model for invasion, initially independent of the ABO group, via the formation of a hybrid A‐like/Tn (T‐nouvelle) structure (different from the specific blood group A epitope), acting as a functional bridge between the spike protein and host mobilization (via TMPRSS2), allowing viral invasion into the host's cell (initial invasion could be present both in group O and non‐O individuals, via the host's GalNac metabolism pathway). After invasion, SARS‐CoV‐2 newly formed virions from group O individuals replace this initial pathway by mucin‐type fucosylation and synthesis of hybrid H‐type antigen, unaffected by innate anti‐A/Tn or anti‐B/Tn isoagglutinins, with a secondary IgG response and reduced viral binding because it happens only via the hybrid‐H‐type antigen since anti‐A or ‐B/Tn isoagglutinins are preserved, explaining the protector effect on group O individuals.…”

Why Blood Group A Individuals Are at Risk Whereas Blood Group O Individuals Might Be Protected from SARS-CoV-2 (COVID-19) Infection: A Hypothesis Regarding How the Virus Invades the Human Body via Abo(H) Blood Group-Determining Carbohydrates

“…Nevertheless, symptom development or subsequent disease severity might depend on the phenotype. Given that O-glycosylation plays a key role in the pathogenesis of the human coronavirus disease, as discussed 14 years ago regarding SARS-CoV-1 infection (Oostra et al, 2006) and is currently predicted for SARS-CoV-2 or COVID-19 (Andersen et al, 2020), would implicate the formation of hybrid, serologically A-like, O-GalNAcα1-Ser/Thr-R, Tn antigenic structures (Arend, P., 2020a). This prediction is not consistent with the concept of Guillon et al (2008), which propose that these viruses bind to hosts using N-glycosylation, although their observation that the interaction between the viral S protein of SARS-CoV-1 and the host's cellular receptor was inhibited by natural and monoclonal anti-A antibodies speaks more for a predominance of the host's Oglycoproteome.…”

Correlation of Body Mass Index (BMI), initial neutralizing antibodies (nAb), ABO group and kinetics of nAb and anti-nucleocapsid (NP) SARS-CoV-2 antibodies in convalescent plasma (CCP) donors – A longitudinal study with proposals for better quality of CCP collections

“…Arend 68 proposed a different model for SARS-CoV-2 invasion, initially independently from ABO group, via the formation of a hybrid A-like/Tn (T-nouvelle) structure (different from the specific blood group A epitope), acting as a functional molecular bridge between the spike protein and host mobilization (via TMPRSS2), allowing the final viral invasion into the host’s cell (initial invasion could be present both in group O and non-O individuals, via the host’s GalNac metabolism pathway). After invasion, SARS-CoV-2 newly formed virions from group O individuals replace this initial metabolic pathway by the mucin-type fucosylation and consequent synthesis of hybrid H-type antigen, being unaffected by the innate anti-A/Tn or anti-B/Tn isoagglutinins, leading to a secondary IgG response; also, viral binding is reduced, because it happens only via the hybrid-H type antigen, since the initial anti-A or -B/Tn isoagglutinins are preserved, possibly explaining the protector effect on group O individuals.…”