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

Infection does not mean disease because for uncountable reasons the invasion of a pathogen does not always lead to disease symptoms. The molecular biology of a virus infection pathogenesis determines the genetic target and the human phenotype-determining enzymes decide about the difference between infection and disease. In the case that O-glycosylation plays a key role in the pathogenesis of coronavirus infections, as was discussed already 14 years ago in a SARS-CoV virus infection and is currently again predicted for SARS-CoV-2 or COVID-19, this would involve the formation of hybrid, serologically A-like, O-GalNAcα1-Ser/Thr-R, Tn (“T nouvelle”) antigenic structures. Although the ACE2 (angiotensin-converting-enzyme 2) protein is defined as the primary SARS-CoV receptor, it is the history of the amino acid serine, suggesting the actual or additional binding via an intermediate hybrid O-glycan: the TMPRSS2 (transmembrane protease serine subtype 2) host protease-mobilized, virus-encoded serine molecule gets access to the host's N-acetyl-D-galactosamine (GalNAc) metabolism and the resulting intermediate, hybrid A-like/Tn structure performs the adhesion of the virus to all nucleated host cells primarily independent of the ABO blood group, while the phenotype-determining sugars become the final glycosidic target. Individuals with blood group A and B cannot respond with preformed innate antibodies to the synthesis of A-like/Tn structures due to phenotypic accommodation of plasma proteins but perform a further (blood group-A- and/or B-specific) hybrid binding, most likely causing autoimmune reactions. A first statistical study suggests that people with blood group A have a significantly higher risk for acquiring COVID-19, whereas people with blood group O have a significantly lower risk for the infection compared with non-O blood groups (Zhao, J. et al., 2020). SARS-Cov-2 (COVID-19) infections may be considered an evolutionary selective disease, contributing to the present-day world distribution of the human ABO(H) blood groups, which has arisen through blood group-related life-threatening diseases over millions of years. While the synthesis of the blood group AB enables the strongest contact with a pathogen and molecularly precluding any isoagglutinin activity, makes this group the least protected and the smallest among the ABO blood groups, blood group O(H) individuals develop the least contact with the pathogen; maintaining the isoagglutinins, they rarer develop severe disease and survive this coevolution in an immunological balance with a pathogen as the largest blood group worldwide. However, it might be speculated that for an unknown period of time they remain pathogen carriers and belong to the main drivers of SARS-CoV-2 pandemic.

Reference: Zhao, J. et al. Relationship between the ABO Blood Group and the COVID-19 Susceptibility. medRxiv (2020) doi:10.1101/2020.03.11.20031096.