Singh, Sumnima; Thompson, Jessica A; Yilmaz, Bahtiyar; Li, Hai; Weis, Sebastian; Sobral, Daniel; Truglio, Mauro; Aires da Silva, Frederico; Aguiar, Sandra; Carlos, Ana Rita; Rebelo, Sofia; Cardoso, Silvia; Gjini, Erida; Nuñez, Gabriel; Soares, Miguel P (2021). Loss of α-gal during primate evolution enhanced antibody-effector function and resistance to bacterial sepsis. Cell host & microbe, 29(3), 347-361.e12. Cell Press 10.1016/j.chom.2020.12.017
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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.
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