Why Are Individuals with Blood Group A at Higher Risk of COVID-19?

New findings published in Blood Advances suggest that SARS-CoV-2, the virus responsible for COVID-19, is particularly drawn to a blood A group antigen on respiratory epithelial cells. However, this apparent preference does not extend to the type of blood group A antigens found on red blood cells (RBCs).

Prior research has shown that the spike protein of SARS-CoV-2 facilitates cell entry through interactions between ACE2 and its RBD, the protein on the surface of the virus that binds to host cells and is responsible for infection. In this study, the investigators hypothesized that the SARS-CoV-2 RBD might interact with other molecules, including blood group antigens.

“It is interesting that the viral receptor-binding domain (RBD) only really prefers the type of blood group A antigens that are on respiratory cells, which are presumably how the virus is entering most patients and infecting them,” said study author Sean R. Stowell, MD, PhD, of Brigham and Women’s Hospital in Boston.

Dr. Stowell also noted that the study was unable to elucidate the underlying mechanism for increased likelihood of infection in individuals with blood type A. “Blood type is a challenge because it is inherited and not something we can change,” he said. “But if we can better understand how the virus interacts with blood groups in people, we may be able to find new medicines or methods of prevention.”

ABO blood group antigens are expressed on RBCs, as well as on the respiratory epithelium and other tissues in the body. The ABO antigens found on RBCs are called type II ABO antigens and differ from the type I ABO antigens found on the respiratory epithelium because of a distinct linkage configuration between the penultimate galactose residue and N-acetylglucosamine. Through glycan microarray, the researchers found that SARS-CoV-2 exhibited a preference for the type I ABO antigens along the respiratory epithelial cells of individuals with blood group A (FIGURE). No preference was observed for the type II ABO antigens of individuals with blood type A, B, or O.

The SARS-CoV-2 RBD is structurally similar to an ancient family of carbohydrate-binding proteins expressed in all metazoans called galectins, which have shown a preference for blood group antigens, the authors noted.

After isolating RBCs from individuals with blood group A, B, or O, the researchers examined whether the RBD displayed similar blood group antigen recognition. The RBD did not show any preference for blood type A RBCs, but binding was observed with ACE2-expressing HEK293 T cells, as well as between anti-A antibody and blood group A RBCs. The authors concluded that binding of SARS-CoV-2 RBD with blood group A antigens on RBCs does not appear to contribute to increased propensity for infection in individuals with blood group A.

In addition to the affinity of SARS-CoV-2 for individuals with blood group A, the investigators found a similar binding specificity of the SARS-CoV RBD for A antigen expressed in the respiratory tract, suggesting that these findings may provide insight into other severe coronaviruses.

The authors noted that the impact of ABO antigen expression on von Willebrand factor levels may also influence thromboembolic complications and disease progression.

Future studies are required to expand upon these findings, as they do not definitively demonstrate that blood group A directly contributes to infection with SARS-CoV-2. “Our observation is not the only mechanism responsible for what we are seeing clinically, but it could explain some of the influence of blood type on COVID-19 infection,” said Dr. Stowell.

The authors report no relevant conflicts of interest.

References

Wu SC, Arthur CM, Wang J, et al. The SARS-CoV-2 receptor-binding domain preferentially recognizes blood group A. Blood Adv. 2021;5(5):1305-1309.