key: cord-1010411-9e4yufo5 authors: Breiman, Adrien; Ruvën-Clouet, Nathalie; Le Pendu, Jacques title: Harnessing the natural anti-glycan immune response to limit the transmission of enveloped viruses such as SARS-CoV-2 date: 2020-05-21 journal: PLoS Pathog DOI: 10.1371/journal.ppat.1008556 sha: 509bb8e8a2851004f8f7f95a7757b189520123a4 doc_id: 1010411 cord_uid: 9e4yufo5 nan domain [10] . The recently emerged SARS-CoV-2 responsible for COVID-19 shows overall conservation of the S protein glycosylation sites. The primary target organ of human coronaviruses, including both SARS and SARS-CoV-2, is the lung and both viruses use angiotensin converting enzyme 2 (ACE2) as receptor [11] . Being expressed on lung alveolar epithelial cells, chiefly type 2 pneumocytes, [12, 13] , it is to be expected that the glycosylation of SARS-CoV and SARS-CoV-2 should be similar. Using a cellular experimental model, our group showed that the interaction between SARS-CoV S protein and ACE2 could be specifically blocked in a dose-dependent manner by anti-A blood group antibodies when the S protein was synthesized by cells that expressed the A histo-blood group antigen following transfection by the appropriate glycosyltransferases cDNA [14] . These observations suggested that, when produced in cells that express the A or B blood group enzymes, infectious SARS virions are decorated by the corresponding glycan antigens and that the presence of anti-A and anti-B antibodies in blood group O individuals could prevent infection by blocking virus attachment and entry. Moreover, blood group O individuals were at a much lower risk of being infected than non-O individuals in a Hong Kong 2003 SARS hospital outbreak [15] , and a similar trend has just been observed for COVID-19 in China [16] . Accordingly, blood group O individuals would be at a lesser risk of being infected than non-O individuals due to blocking of potential transmission events from either A, B, or AB individuals, providing anti-A or anti-B titers are of sufficient magnitude (Fig 1) . Mathematical modeling of the consequences of this potential limitation of virus transmission suggested that the Hong Kong SARS hospital outbreak had been slowed down to some extent thanks to the ABO genetic polymorphism and the ensuing neutralizing anti-A and anti-B antibodies. It further indicated that if anti-blood group A and/ or B titers had always been high, transmission of the virus, in the absence of any containment measure, would be largely impaired and the outbreak slowed to a considerable extent [14] . We therefore hypothesize that as they are produced in cells coexpressing the ACE2 receptor and either the αGal, NeuGc, or A/B blood group antigens, both SARS-CoV and SARS-CoV2 harbor the corresponding glycan epitopes. Because of the natural immune response against these epitopes, the αGal and NeuGc xenoantigens would contribute to prevent cross-species transmission from nonprimate mammals to humans, while A/B blood group antigens would contribute to decrease and slow between-human transmission. Nonetheless, owing to the presence of individuals with low anti-αGal titers, occasional cross-species transmission may occur. Interestingly, a recent genomic analysis across vertebrates revealed that two bats lineages, including Rhinopholus bats suspected to have originated the SARS-CoV-2 closest ancestor, lost their Cmah gene function, similar to humans [17] . The lack of NeuGc xenoantigen on the virions produced by these bats might have facilitated cross-species transmission. Likewise, impairment of transmission by the anti-blood group antibodies may not work to its full potential because of their variable titers in the population and of the high affinity of the SARS-CoV2 for ACE2 [18] , rendering its neutralization more difficult. This leaves room to amplify these innate mechanisms of protection in preparation for the next emergence and mitigation of the virus impact once emergence has occurred. If the antibody blocking effect can be documented in vitro, and possibly in vivo, it will become important to consider raising the anti-αGal, as well as the anti-A and anti-B antibodies titers in human populations. That could be achieved as previously described either by immunizing against inactivated harmless bacteria that harbor the αGal, A, and B epitopes or by immunizing against the corresponding synthetic oligosaccharides linked to an immunogenic scaffold [19, 20] . Raising the anti-A and anti-B titers in the whole population carries the risk of complicating incompatible platelet transfusion as well as increasing the risk of hemolytic disease of the newborn in case of mother-infant ABO incompatibility. These issues should be carefully dealt with. Raising the anti-NeuGc titers might be more problematic since meat and dairy products consumption allows incorporation of NeuGc onto human glycans, and this may contribute to the promotion of inflammation and cancer progression as experimentally demonstrated [3, 21] . By contrast, raising the anti-αGal titers should not carry any risk since the antigen is entirely absent from human tissues. Blood groups A and B might also be harnessed to increase the efficacy of SARS-CoV-2 vaccines. Indeed, the virus spike proteins, which are the main target of currently designed vaccines, might be produced in cells that are enzymatically equipped to synthetize A and B antigens so that the vaccine glycoprotein will carry these epitopes. In addition to generating neutralizing anti-S protein, the vaccine would stimulate anti-A and anti-B responses that may contribute to the vaccine efficacy in all cases of ABO incompatible transmissions. In conclusion, we propose to enhance the innate anti-viral protection conferred by natural anti-glycan antibodies in order to lower both the risk of emergence of coronaviruses, or other enveloped viruses, from a nonprimate mammalian species and the risk of transmission within the human population. This could add-up to other protection and containment measures, mitigating the impact of the epidemic. Virions produced by blood group O individuals are devoid of A or B antigens and can be fully transmitted regardless of the recipient blood type (full arrows). Viruses produced by A and B blood groups individuals are decorated by A or B blood group epitopes (red and green spikes, respectively) and viruses produced by blood group AB individuals are decorated by both A and B epitopes. Transmission of such viruses will be decreased by the presence of either anti-A and/or anti-B of the recipient (dashed arrows). Transmission between individuals of the same subtype will always be maximal (circular arrows). In the presence of high-titered anti-A and anti-B antibodies, transmissions represented by dashed arrows should be completely ablated. https://doi.org/10.1371/journal.ppat.1008556.g001 Evolution of carbohydrate antigens-microbial forces shaping host glycomes? 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A first step in understanding SARS pathogenesis Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov Inhibition of the interaction beteen the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies ABO blood group and susceptibility to severe acute respiratory syndrome Relationship between the ABO Blood Group and the COVID-19 Susceptib Phylogenetic Distribution of CMP-Neu5Ac Hydroxylase (CMAH), the Enzyme Synthetizing the Proinflammatory Human Xenoantigen Neu5Gc Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Induction of cytolytic anti-gal antibodies in α-1,3-galactosyltransferase gene knockout mice by oral inoculation with Escherichia coli O86: B7 bacteria Development of a-Gal-Antibody Conjugates to Increase Immune Response by Recruiting Natural Antibodies A red meat-derived glycan promotes inflammation and cancer progression The authors are grateful to Hanane El Kenz (Brugmann University Hospital, Brussels, Belgium) and France Pirenne (Henri Mondor University Hospital, Créteil, France) for fruitful discussions and helpful remarks.