Abstract
Human natural antibodies to mammalian carbohydrate antigens (MCA) bind to carbohydrate-antigens synthesized in other mammalian species and protect against zoonotic virus infections. Three such anti-MCA antibodies are: (1) anti-Gal, also produced in Old-World monkeys and apes, binds to α-gal epitopes synthesized in non-primate mammals, lemurs, and New-World monkeys; (2) anti-Neu5Gc binds to Neu5Gc (N-glycolyl-neuraminic acid) synthesized in apes, Old-World monkeys, and many non-primate mammals; and (3) anti-Forssman binds to Forssman-antigen synthesized in various mammals. Anti-viral protection by anti-MCA antibodies is feasible because carbohydrate chains of virus envelopes are synthesized by host glycosylation machinery and thus are similar to those of their mammalian hosts. Analysis of MCA glycosyltransferase genes suggests that anti-Gal appeared in ancestral Old-World primates following catastrophic selection processes in which parental populations synthesizing α-gal epitopes were eliminated in enveloped virus epidemics. However, few mutated offspring in which the α1,3galactosyltransferase gene was accidentally inactivated produced natural anti-Gal that destroyed viruses presenting α-gal epitopes, thereby preventing extinction of mutated offspring. Similarly, few mutated hominin offspring that ceased to synthesize Neu5Gc produced anti-Neu5Gc, which destroyed viruses presenting Neu5Gc synthesized in parental hominin populations. A present-day example for few humans having mutations that prevent synthesis of a common carbohydrate antigen (produced in >99.99% of humans) is blood-group Bombay individuals with mutations inactivating H-transferase; thus, they cannot synthesize blood-group O (H-antigen) but produce anti-H antibody. Anti-MCA antibodies prevented past extinctions mediated by enveloped virus epidemics, presently protect against zoonotic-viruses, and may protect in future epidemics. Travelers to regions with endemic zoonotic viruses may benefit from vaccinations elevating protective anti-MCA antibody titers.
Highlights
Natural antibodies in humans are continuously produced without active vaccination
This review describes three of the most studied anti-mammalian carbohydrate antigens (MCA) antibodies, readily detected in humans (Table 1), namely anti-Gal, anti-N-glycolyl neuraminic acid, and anti-Forssman antibodies, all found in healthy individuals
In-vitro complement mediated virus killing by anti-Gal binding to α-gal epitopes on viral envelope glycoproteins was observed upon incubation in human serum of several types of enveloped viruses, including: Type C retrovirus [66], porcine endogenous retrovirus (PERV) [67,68], vesicular stomatitis virus (VSV) [62,69,70], lymphocytic choriomeningitis virus, Newcastle disease virus, Sindbis virus [70], Pseudorabies virus (PrV—a member of herpesviridae α-herpes subfamily) [71], measles virus [72,73], and vaccinia virus [74], all produced in host-cells with active α1,3GT
Summary
Natural antibodies in humans are continuously produced without active vaccination. The much higher susceptibility to viral and bacterial infections of mice lacking immunoglobulins compared to mice producing natural antibodies led to the suggestion that “Natural antibodies are often dismissed from immunological analysis as ‘background’, but they may play an important role in conferring immunity against infections” [1]. This review describes a group of human natural anti-carbohydrate antibodies of particular significance, which may be regarded as “unsung heroes” that function as an important first line of immune defense in humans against zoonotic enveloped viruses. They are produced against bacterial carbohydrate-antigens, these natural antibodies bind to mammalian carbohydrate-antigens (MCA) produced in species other than humans. Based on the mammalian distribution patterns of these antibodies, on their corresponding MCA ligands, and on the characteristics of the genes coding enzymes that synthesize these antigens, this review further suggests that natural anti-MCA antibodies protected ancestral primates from extinction in past epidemics of deadly enveloped viruses and presently continue such a protection. Anti-H serves as a present-day example which simulates the potential of anti-MCA antibodies in preventing extinctions of few mutated primates during deadly viral epidemics and may have a similar role in future epidemics
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