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

Cell Host Microbe. 2021 Mar 10;29(3):347-361.e12. doi: 10.1016/j.chom.2020.12.017. Epub 2021 Jan 25.


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.

Keywords: IgG effector function; glycans; human evolution; infection; microbiota; natural antibodies; reproductive senescence; sepsis; trade-off; α-gal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria
  • Biological Evolution*
  • Carrier Proteins
  • DNA-Binding Proteins
  • Disaccharides*
  • Female
  • Galactosyltransferases / genetics
  • Galactosyltransferases / metabolism
  • Glycoproteins
  • Hominidae
  • Humans
  • Immunoglobulin G / immunology
  • Male
  • Mammals / immunology
  • Mice
  • Mice, Knockout
  • Polysaccharides
  • Primates
  • Sepsis / microbiology*


  • Carrier Proteins
  • DNA-Binding Proteins
  • Disaccharides
  • Glycoproteins
  • Immunoglobulin G
  • Polysaccharides
  • Rag2 protein, mouse
  • galactosyl-(1-3)galactose
  • Galactosyltransferases
  • N-acetyllactosaminide alpha-1,3-galactosyltransferase