| First Author | Singh S | Year | 2021 |
| Journal | Cell Host Microbe | Volume | 29 |
| Issue | 3 | Pages | 347-361.e12 |
| PubMed ID | 33497603 | Mgi Jnum | J:308053 |
| Mgi Id | MGI:6719482 | Doi | 10.1016/j.chom.2020.12.017 |
| Citation | Singh S, et al. (2021) Loss of alpha-gal during primate evolution enhanced antibody-effector function and resistance to bacterial sepsis. Cell Host Microbe 29(3):347-361.e12 |
| abstractText | Most mammals express a functional GGTA1 gene encoding the N-acetyllactosaminide alpha-1,3-galactosyltransferase enzyme, which synthesizes Gal-alpha1-3Gal-beta1-4GlcNAc (alpha-gal) and are thus tolerant to this self-expressed glycan. Old World primates including humans, however, carry loss-of-function mutations in GGTA1 and lack alpha-gal. Presumably, fixation of such mutations was propelled by natural selection, favoring the emergence of alpha-gal-specific immunity, conferring resistance to alpha-gal-expressing pathogens. Here, we show that loss of Ggta1 function in mice enhances resistance to bacterial sepsis, irrespectively of alpha-Gal-specific immunity. Rather, the absence of alpha-gal from IgG-associated glycans increases IgG effector function via a mechanism associated with enhanced IgG-Fc gamma receptor (FcgammaR) binding. The ensuing survival advantage against sepsis comes alongside a cost of accelerated reproductive senescence in Ggta1-deleted mice. Mathematical modeling of this trade-off suggests that high exposure to virulent pathogens exerts sufficient selective pressure to fix GGTA1 loss-of-function mutations, as likely occurred during the evolution of primates toward humans. |
