Harnessing the natural anti-glycan immune response to limit the transmission of enveloped viruses such as SARS-CoV-2

Abstract

Enveloped viruses are glycosylated, meaning that their envelope proteins are post-translationally modified by the addition of glycans. Some glycosyltransferases that contribute to terminate glycan chains synthesis are differentially expressed between cell types within or between species, which bears important immunological consequences A prime example concerns the GGTA1 gene encoding a galactosyltransferase that catalyzes the transfer of a galactose in 1,3 linkage onto subterminal N-acetyllactosamines. This glycosyltransferase is expressed by all mammals except Old World monkeys, apes and humans, due to inactivating mutations that occurred in a common primate ancestor some 20 to 40 million years ago. Consequently, all humans lack the Gal glycan motif and possess natural anti-Gal antibodies generated in response to bacteria of the microbiota that express similar glycans Likewise, humans lack expression of the N-glycolyl form of sialic acid (NeuGc) due to a pseudogenization event of the CMAH gene that occurred about 2 million years ago. In most other animal species, the orthologous gene encodes the cytidine monophosphate (CMP)-NeuAc hydroxylase that converts NeuAc into NeuGc from the nucleotide form CMP-NeuAc. As a result of our inability to synthesize NeuGc, natural anti-NeuGc are also present in humans (reviewed in Another example concerns the enzymes that are involved in the synthesis of the ABO histo-blood group antigens. The A and B enzymes catalyze the transfer of an N-acetylgalactosamine and a galactose, respectively, in 1,3 linkage on a precursor structure called the H antigen, generating the corresponding A or B antigens. They are encoded by distinct alleles at the ABO locus. The O alleles are null alleles responsible for a lack of transferase, in which case the H antigen remains unchanged. O alleles in the homozygote state confer blood group O, which is characterized by a complete absence of A or B antigens Under stimulation by bacteria of the microbiota that present glycan motifs similar to either A or B antigens, blood group O people develop so-called "natural" anti-A and anti-B antibodies, whilst blood group A and B individuals develop either anti-B or anti-A antibodies, respectively Only people of the AB subgroup lack such antibodies. In humans, besides their expression on red blood cells, ABH antigens are widely expressed on many other cell types, including vascular endothelial cells and epithelial cells of many organs Importantly, the titers of anti-Gal, anti-NeuGc, and anti-A/B antibodies are highly variable between individuals, ranging from 100-to 1000-fold