2. Academic Validation
  3. Loss of α-gal during primate evolution enhanced antibody-effector function and resistance to bacterial sepsis

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.
Sumnima Singh 1,  Jessica A Thompson 1,  Bahtiyar Yilmaz 2,  Hai Li 3,  Sebastian Weis 4,  Daniel Sobral 1,  Mauro Truglio 1,  Frederico Aires da Silva 5,  Sandra Aguiar 5,  Ana Rita Carlos 6,  Sofia Rebelo 1,  Silvia Cardoso 1,  Erida Gjini 1,  Gabriel Nuñez 7,  Miguel P Soares 8
Affiliations

Affiliations

  • 1 Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
  • 2 Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal; Maurice Müller Laboratories (DBMR), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, 3008 Bern, Switzerland.
  • 3 Maurice Müller Laboratories (DBMR), Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, University of Bern, 3008 Bern, Switzerland.
  • 4 Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal; Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital Friedrich-Schiller University, 07747 Jena, Germany.
  • 5 Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, 1300-477 Lisbon, Portugal.
  • 6 Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal; Departamento de Biologia Animal, Centro de Ecologia, Evolução e Alterações Ambientais, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisbon, Portugal.
  • 7 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • 8 Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal. Electronic address: [email protected].
PMID: 33497603 DOI: 10.1016/j.chom.2020.12.017
Abstract

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.

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