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

• Published in: Medical hypotheses Vol. 144; p. 110168
• Main Author: Murch, Simon H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.11.2020; The Author. Published by Elsevier Ltd
• Subjects: Alleles; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Antiviral Agents - therapeutic use; Child; COVID-19 - immunology; COVID-19 - metabolism; COVID-19 - virology; Disease Progression; Female; Genotype; Humans; Immunity, Innate; Inflammasomes; Inflammation; Lectins - metabolism; Ligands; Male; Models, Theoretical; Mutation; Polymorphism, Genetic; Polysaccharides - chemistry; Protein Binding; SARS-CoV-2; Sex Factors; Sialic Acid Binding Ig-like Lectin 3 - metabolism; Spike Glycoprotein, Coronavirus - metabolism; Systemic Inflammatory Response Syndrome - immunology
• ISSN: 0306-9877; 1532-2777
• DOI: 10.1016/j.mehy.2020.110168

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.