Possible Role of a Cell Surface Carbohydrate in Evolution of Resistance to Viral Infections in Old World Primates

Abstract

bDue to inactivation of the ␣1,3-galactosyltransferase gene (GGTA1, or the ␣1,3GT gene) approximately 28 million years ago, the carbohydrate ␣Gal (Gal␣1,3Gal␤1,4GlcNAc) is not expressed on the cells of Old World monkeys and apes (including humans) but is expressed in all other mammals. The proposed selective advantage of this mutation for these primates is the ability to produce anti-Gal antibodies, which may be an effective immune component in neutralizing ␣Gal-expressing pathogens. However, loss of ␣1,3GT expression may have been advantageous by providing natural resistance against viral pathogens that exploited the ␣1,3GT pathway or cell surface ␣Gal for infection. Infections of paired cell lines with differential expression of ␣1,3GT showed that Sindbis viruses (SINV) preferentially replicate in ␣1,3GT-positive cells, whereas herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) preferentially grow in cells lacking ␣1,3GT. Viral growth and spread correlated with the ability of the different viruses to successfully initiate infection in the presence or absence of ␣1,3GT expression. GT knockout (KO) suckling mice infected with SINV strains (AR339 and S.A.AR86) experienced significant delay in onset of disease symptoms and mortality compared to wild-type (WT) B6 suckling mice. In contrast, HSV-2-infected GT KO mice had higher viral titers in spleen and liver and exhibited significantly more focal hepatic necrosis than WT B6 mice. This study demonstrates that ␣1,3GT activity plays a role in the course of infections for certain viruses. Furthermore, this study has implications for the evolution of resistance to viral infections in primates.

Virus-like Particle Display of the α-Gal Carbohydrate for Vaccination against Leishmania Infection

“…Since only humans and higher apes among all mammals lack the α-galactosyltransferase gene, the αGalT-KO mouse mimics the human immune system’s ability to generate anti-α-Gal antibodies to a much greater degree than wild-type rodents. These mice have been used primarily in studies of xenotransplant rejection and fertilization, , but are also of great potential interest for studies of any pathogen that displays α-Gal.…”

Why Do We Produce Anti-Gal

“…A current example for such a virus is bovine norovirus that was reported to use α-gal epitopes as a docking receptor for infecting bovine cells (Zakhour et al, 2009). In addition, Sindbis virus was found to preferentially infect cells that present α-gal epitopes and wild-type suckling mice synthesizing this epitope, in comparison with cells or suckling mice lacking α-gal epitopes (Rodriguez and Welsh, 2013).…”

Alpha-Gal Bound Aptamer and Vancomycin Synergistically Reduce Staphylococcus aureus Infection In Vivo

“…This consistent α-gal exposure in humans leads to high levels of anti-α-gal Abs, comprising up to 10% of total circulating Abs and up to 1% of total IgG in humans [ 19 , 20 , 25 ]. In an evolutionary context, anti-α-gal Abs may have emerged as Old World monkeys faced viruses, taking advantage of the hosts own α-gal surface modification [ 26 ]. Thus, simultaneously losing the ability to produce α-gal epitopes and creating Abs capable of flagging these invaders became an advantageous way to fend off viruses [ 26 ].…”