Common determinants of severe Covid-19 infection are explicable by SARS-CoV-2 secreted glycoprotein interaction with the CD33-related Siglecs, Siglec-3 and Siglec-5/14

Abstract

SARS-CoV-2 interaction with the ACE-2 receptor cannot alone explain the demography and remarkable variation in clinical progression of Covid-19 infection. Unlike SARS-CoV, the cause of SARS, several SARS-CoV-2 spike glycans contain sialic acid residues. In contrast to the SARS secreted glycoprotein (SGP), SARS-CoV-2 SGP are thus potential ligands for Sialic acid-binding Siglecs on host immune cells, known to regulate immune function. Such SARS-CoV-2 glycoproteins would contribute to immune deviation. CD33-related Siglecs are important immune regulators. Siglec-5 and −14 are paired receptors with opposed actions on the NLRP3 inflammasome, which is critical in early viral clearance. SGP binding in persons of Siglec-14 null genotype (30–70% in Black, Asian and Minority Ethnic (BAME) persons, 10% in North Europeans) would induce unopposed inhibitory signalling, causing viral persistence through inflammasome inhibition. Siglec-3 (CD33) and Siglec-5 are expressed on CD33 myeloid derived suppressor cells (CD33 MDSC). Immunosuppressive CD33 MDSC populations are increased in all groups at risk of severe Covid-19 infection. CD33 expression is increased in persons with the CD33 rs3865444 CC allele, associated with Alzheimer’s disease, who would thus show enhanced susceptibility. Viral SGP ligation of CD33, potentially in conjunction with Siglec-5, would promote expansion of CD33 MDSC cells, as occurs in cancers but at much greater scale. CD33 is expressed on CNS microglia, potentially activated by SGP penetration through the porous cribriform plate to cause anosmia. Genotyping of severe or fatal Covid-19 cases can confirm or refute this pathophysiological mechanism. Early data have confirmed extremely high-level increase of CD33 MDSC numbers in severe Covid-19 infection, consistent with the proposed mechanism.

Enhanced expression of immune checkpoint receptors during SARS-CoV-2 viral infection

“…Glycosylation mappings have revealed that unlike SARS-CoV-1, SARS-CoV-2 has a sialic acid residue in its spike glycans. 103 Sialic acid recognizes CD33-related SIGLECs (hCD33rSiglecs), including SIGLEC3 and SIGLEC5-SIGLEC11, and it has intra-cellular domains with an inhibitory ITIM or ITIM-like motif. Further investigations are needed to determine how the increase in expression of these myeloid IRs could affect the course of SARS-CoV-2 viral infection.…”

The impact of DAMP-mediated inflammation in severe COVID-19 and related disorders

“…1 ). For instance, sialylated secreted glycoproteins from SARS-CoV-2 can bind to and activate host Siglecs thus downregulating the antiviral response [104] . Furthermore, SARS-CoV-2 viral spike proteins contain α2,6 and α2,3 linked sialic acids that enable their interaction with Siglec-1, Siglec-3, Siglec-9, and Siglec-10, facilitating their entry into host immune cells [19] , [105] , a phenomenon which can be blocked with an anti-Siglec-1 monoclonal antibody [19] ( Figure.…”

Effects of Bacille Calmette Guerin (BCG) vaccination during COVID-19 infection

“…Yong et al reported increased expression of pro-inflammatory cytokines including CXCL1 and CXCL8 as well as chemokine CCL4 and CCR2 in SARS-CoV-2 infected patients [ 73 ]. Higher expression of CD33 is reported to be associated with the increased severity of COVID-19 [ 74 ]. An enhanced ratio of IFNG has been found in severe SARS-CoV-2 infected patients, which could exacerbate the cytokine storm [ 75 ].…”