The antibody response to the glycan α-Gal correlates with COVID-19 disease symptoms

Abstract

The coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide. The characterization of the immunological mechanisms involved in disease symptomatology and protective response is important to advance in disease control and prevention. Humans evolved by losing the capacity to synthesize the glycan Galα1-3Galβ1-(3)4GlcNAc-R (α-Gal), which resulted in the development of a protective response against pathogenic viruses and other microorganisms containing this modification on membrane proteins mediated by anti-α-Gal IgM/IgG antibodies produced in response to bacterial microbiota. In addition to anti-α-Gal antibody-mediated pathogen opsonization, this glycan induces various immune mechanisms that have shown protection in animal models against infectious diseases without inflammatory responses. In this study, we hypothesized that the immune response to α-Gal may contribute to the control of COVID-19. To address this hypothesis, we characterized the antibody response to α-Gal in patients at different stages of COVID-19 and in comparison with healthy control individuals. The results showed that while the inflammatory response and the anti-SARS-CoV-2 (Spike) IgG antibody titers increased, reduction in anti-α-Gal IgE, IgM and IgG antibody titers and alteration of anti-α-Gal antibody isotype composition correlated with COVID-19 severity. The results suggested that the inhibition of the α-Gal-induced immune response may translate into more aggressive viremia and severe disease inflammatory symptoms. These results support the proposal of developing interventions such as probiotics based on commensal bacteria with α-Gal epitopes to modify the microbiota and increase the α-Gal-induced protective immune response and reduce the severity of COVID-19.

Abnormal antibodies to self-carbohydrates in SARS-CoV-2 infected patients

“…A previous study by Urra et al reported an inverse correlation for IgG and IgM antibodies to alpha-Gal[Galα1-3Galβ1-3(4)GlcNAc] and COVID-19 disease severity; those with the most severe outcomes had the lowest levels of α-Gal antibodies. 45 In their study, COVID-19 patients as a group had lower antibody levels than healthy subjects. Conversely, our results demonstrated higher overall mean α-Gal IgG antibodies (Figure 8 and Figure S7).…”

“…[36][37][38][39] Another recent study reported an inverse relationship between COVID-19 disease severity and serum anti-α-Gal antibodies. 45 α-Gal is a non-human glycan, and natural antibodies to this glycan epitope can be part of the protective response to pathogenic viruses, bacteria, and parasites that contain this glycan. [45][46][47][48] In addition to these studies on serum anti-carbohydrate antibodies, several studies have demonstrated that the SARS-CoV-2 spike protein is heavily glycosylated.…”

“…45 α-Gal is a non-human glycan, and natural antibodies to this glycan epitope can be part of the protective response to pathogenic viruses, bacteria, and parasites that contain this glycan. [45][46][47][48] In addition to these studies on serum anti-carbohydrate antibodies, several studies have demonstrated that the SARS-CoV-2 spike protein is heavily glycosylated. [49][50][51][52][53][54] Glycosylation mapping of the spike protein subunits revealed a variety of O-linked and N-linked glycans, including highmannose.…”

Reply to: The antibody response to the glycan α‐Gal correlates with COVID‐19 symptoms

“…5,6 On this backdrop, Urra et al reported that patients with COVID-19 had altered levels of anti-α-Gal IgG, IgM, IgA, and IgE Ab as compared to a control cohort. 1 Specifically, they found that levels of α-Gal-specific IgG, IgM, and IgE (but not IgA), were lower in patients hospitalized in an intensive care unit (ICU) with severe COVID-19 as compared to healthy uninfected controls. They also reported that relative amounts of different anti-α-Gal antibody isotypes varied in relation to disease severity.…”

“…We read with interest two recent papers which discussed possible connections between the immune response to galactose-α-1,3galactose (α-Gal) and coronavirus disease 2019 (COVID-19). 1,2 First described nearly a hundred years ago by Landsteiner and Miller as a "B-like" blood group substance of non-primate mammals (but not higher primates), work over the last 40 years has made it clear that α-Gal is also expressed on some species of bacteria and multi-cellular parasites, and that all immunocompetent humans produce large quantities of immunoglobulin M (IgM), IgG and IgA antibodies (Ab) specific for the oligosaccharide. 3,4 More recent research indicates that a subset of the population can also produce IgE specific for α-Gal.…”