The infectious capacity of SARS-CoV-2 has been characterized previously. The virus binds to the cell surface via its S protein, cell receptor-binding domains (RBDs), and virus-cell membrane fusion domains (35). The S protein binds to the host cell receptor's ACE2 (36). ACE2 is present in virtually all organs, but lung alveolar epithelial cells and enterocytes of the small intestine (37) are important in this context. Moreover, the transmembrane protease serine subfamily member 2 (TMPRSS2), a cell surface protein expressed by endothelial cells in the respiratory and digestive tracts, is used by the virus for S protein priming (38). Enhanced entry correlated with optimal functions of both TMPRSS2 and ACE2. Similarly, in ACE2 expressing cells, dendritic-cell-specific ICAM3-grabbing nonintegrin (DC/L-SIGN) facilitates the infectious capacity; however, an adequate ACE2 correlation is required (39). These mechanisms promulgated in SARS-CoV-2 have also been confirmed in COVID-19 (40, 41). ACE2 is the main host cell receptor for the viral S protein (no other receptor has been discussed), and its function is probably improved by the proper interaction between TMPRSS2 and DC/L-SIGN (42).

Immunoglobulins can bind to or block different proteins. Anti-A and anti-B antibodies from the ABO system are natural Igs in serum. It has been reported that the presence of anti-A antibodies (and probably anti-B antibodies) prevents the interaction between the viral S protein of the virus and ACE2 on the cell surface (Figure 1). The molecular mechanism is not yet fully understood. However, several hypotheses have been proposed. It seems that carbohydrates or glycosylated epitopes are present in the cell membrane of both SARS-CoV-2 and ACE2 and it is known the strong binding between natural antibodies from the ABO system and carbohydrate molecules, such as A or B antigens. On the one hand, the S protein could be decorated with A or B carbohydrate epitopes able to be recognized by the natural anti-A or -B antibodies from blood group O, B, and A individuals (24). On the other hand, natural anti-A or -B antibodies can directly bind to the ACE2 glycosylated region (43). In this case, possible competitive inhibition of ACE2 by both natural (anti-A/anti-B) antibodies and SARS-CoV-2 may induce early ACE2 downregulation in blood group O, increasing the production of multiple inflammatory cytokines (44) in the first step of the infection. Patients with the O blood group suffered a consequent cytokine drop during the hospital stay, while non-O patients maintained their cytokine levels associated with hyperinflammation. An early, effective, and moderate cytokine release functions in immunocompetent patients, while disease severity is linked to persistent immune dysregulation after infection, associated with high cytokine levels for days or weeks. These findings could explain the optimal activation of the immune response and the effective viral clearance of SARS-CoV-2 infection in the patients with the O blood group. In any case, the interaction between natural antibodies and ACE2 or S proteins should prevent viral infection via transfusion rules. Therefore, natural anti-A or -B antibodies protect patients with the O blood group against severe disease and mortality in COVID-19. Comparatively, antibodies operate via the same mechanism as future specific treatments against SARS-CoV-2 (45). The more anti-A or-B antibodies present in the plasma (O blood group), the reduced infectious capacity (19). In contrast, the absence of antibodies (AB blood group) or one of them (A or B blood groups) is associated with a higher risk for poor outcomes in COVID-19 (20). Descriptive and epidemiological studies have corroborated this tendency during the pandemic in all populations (15, 17, 18, 20–22, 32, 33, 46).

Natural anti-A or -B antibodies from the ABO system differ from most naturally occurring antibodies because of their exclusive expression in individuals lacking the corresponding antigen (A or B antigen)(47). They exhibit high polyspecificity and polyreactivity to multiple antigens, not only those included in the ABO system (48). The main isotype of natural Ig is M (IgM) in all ABO blood groups with specific natural antibodies (A, B, and O blood groups), reaching all groups with similar plasma concentrations of IgM antibodies. By cons, the presence of anti-A/B antibodies with the IgG isotype was restricted to the O blood group (Figure 2). Indeed, anti-A or anti-B IgG were found in almost 90% (34/38) of O blood group donors (predominance of IgG2). Meanwhile, only 14% of patients with the A blood group had anti-B IgG, and 4% with B blood group had anti-A IgG. None of the AB blood group samples contained anti-A or anti-B antibodies of any isotype (IgM or IgG) (25). Until now, there has been no explanation for this finding. It would be relevant, for example, in hemolytic disease of the newborn because only newborns of blood group O mothers develop the hemolytic disease after ABO-incompatible pregnancies (49). In COVID-19, studies have shown that patients with the O blood group are under-represented, whereas patients with groups A, B, and AB are over-represented (20). We previously explained that the higher the plasma concentration of natural anti-A or anti-B antibodies (O blood group), the higher the protective effect against SARS-CoV-2 infection. Nevertheless, it is not only the plasma level of natural antibodies but also the isotype of Ig. IgG (restricted to the O blood group) may strongly avoid the interaction between ACE2 and the S protein compared to the IgM isotype.

A strong immune system is crucial for overcoming infections. It includes both an optimal innate and adaptive immune response, with adequate antibody production by B cells. Unfortunately, many situations can weaken the immune system, reducing cell-mediated immune function and humoral immune responses. This decline in immune capacity is associated with reduced antibody levels, making individuals more suitable for infections and disease severity. Older individuals are one of the most recognized cases (9). Aging reduces the production of B and T cells in the bone marrow and thymus and diminishes the function of mature lymphocytes in secondary lymphoid tissues (50). Similarly, immunosuppressive treatments (glucocorticoids, cytotoxic drugs, other immunomodulatory agents, or new immunosuppressive therapies) can also compromise the immune system (51). In addition, infections can have immunosuppressive effects in the local environment (52), increasing susceptibility and severity of infectious diseases and decreasing the efficacy of vaccination (53). Moreover, different studies have revealed, in severe cases of COVID-19, that the presence of immune downregulation with profound immunosuppression was the primary phenomenon. Immunological alterations vary and are classified into different subsets or phenotypes. One of these immunophenotypes is characterized by the coexisting alterations in T cells' numbers, subset composition, cycling, activation, and gene expression (54, 55).

It has been shown for SARS-CoV that the interference between natural anti-A antibodies in the O blood group was dose-dependent and still detected at a plasma dilution of up to 1/32. Indeed, patients with the O blood group with low anti-A antibodies were not inhibitory in the host cell adhesion assay (24). The lack of or drop in antibodies due to any immunosuppressive situation creates ABO discrepancies (56). Therefore, it is of value to determine whether the ABO group performed both forward (red blood cell antigen) and reverse (anti-A and anti-B antibodies in plasma). Once we know the importance of natural antibodies from the ABO system in COVID-19, we should evaluate only the reverse type in terms of protection against viral infection. Accordingly, patients with the O, A, or B blood groups (forward type) that associate lack of antibodies would behave as the AB blood group (reverse type). The current situation favors infections and worsens outcomes for a large number of people, especially older adults and patients who are immunosuppressed.

While aging decreases plasma levels of antibodies, studies have demonstrated increased ACE2 and TMPRSS2 expression in older adults (10, 57). The first study described a significant expression of ACE2 in older males in both mouse models and human organs (10). The second study demonstrated the overexpression of ACE2 and TMPRSS2 in the upper respiratory tract of aged ferrets compared to young animals (57). Moreover, a recent study found that ACE2 levels increase during aging in mouse and human lungs due to telomere shortening or dysfunction (58). It involves the transcriptional level, where ACE2 promoter activity is dependent on DNA damage response (58). Therefore, both the upregulation of ACE2 and the decrease in antibodies make the elderly more susceptible to severe infection by SARS-CoV-2 (Figure 2).