Loss of α-gal during primate evolution enhanced antibody-effector function and resistance to bacterial sepsis

Most mammals express a functional GGTA1 gene encoding the N-acetyllactosaminide α-1,3-galactosyltransferase enzyme, which synthesizes Gal-α1-3Gal-β1-4GlcNAc (α-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 α-gal. Presumably, fixation of such mutations was propelled by natural selection, favoring the emergence of α-gal-specific immunity, conferring resistance to α-gal-expressing pathogens. Here, we show that loss of Ggta1 function in mice enhances resistance to bacterial sepsis, irrespectively of α-Gal-specific immunity. Rather, the absence of α-gal from IgG-associated glycans increases IgG effector function via a mechanism associated with enhanced IgG-Fc gamma receptor (FcγR) 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. [Display omitted] •Human ancestors lost GGTA1 function and α-gal glycan expression•Loss of IgG-associated α-gal enhances resistance to bacterial sepsis•Loss of GGTA1 function precipitates reproductive senescence•The fitness gain of GGTA1 loss function can outweigh its reproductive cost Singh et al. propose that loss α-gal expression was naturally selected in ancestral primates based on enhanced resistance to bacterial sepsis due to α-gal “removal” from IgG. Despite early onset of reproductive senescence in absence of α-gal, mathematical modeling suggests that the survival advantage against infection outweighed this trade-off.