A trade-off between resistance to infection and reproduction in primate evolution

Abstract

Most mammals express a functional GGTA1 gene encoding the N-acetyllactosaminide α-1,3-galactosyltransferase enzyme, which synthesizes Galα1-3Galβ1-4GlcNAc (αGal) and are thus tolerant to this self-expressed glycan epitope. Old World primates including humans, however, carry GGTA1 loss-of-function mutations and lack αGal. Presumably, fixation of such mutations was propelled by natural selection, favoring the emergence of αGal-specific immunity, which conferred resistance to αGal-expressing pathogens. Here we show that loss of Ggta1 function in mice enhances resistance to bacterial sepsis, irrespectively of αGal-specific immunity. Rather, the absence of αGal 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 earlier onset of reproductive senescence. Mathematical modeling of this trade-off shows that under conditions of high exposure to virulent pathogens, selective pressure can fix GGTA1 loss-of-function mutations, as likely occurred during the evolution of primates towards humans.

Glycan-Based Shaping Of The Microbiota During Primate Evolution

“…Crossing of F 0 J h t +/+ Ggta1 +/+ (female) with J h t -/-Ggta1 -/-(male) mice produced F 1 J h t +/-Ggta1 +/mice, which were interbred to generate F 2 J h t +/+ Ggta1 +/+ , J h t +/+ Ggta1 -/-, J h t -/-Ggta1 +/+ and J h t -/-Ggta1 -/mice, harboring a microbiota composition indistinguishable among genotypes ( Figure S7A,B). Consistent with our previous observations ( Figure 1C) (Singh et al, 2020), this suggests that maternal Ig transfer predominates over offspring Ig production in shaping the offspring microbiota, regardless of the genotype (Ubeda et al, 2012).…”

“…Mice were genotyped from tail biopsies (0.5-1 cm) by PCR of genomic DNA as per manufacturer's protocols (KAPA mouse genotyping kit #KK7352) as described (Singh et al, 2020).…”

“…Quantification of pathogen load in the mice was performed 24 h after cecal slurry injection, essentially as described (Singh et al, 2020).…”

“…Bacterial DNA from fecal pellets was extracted according to manufacturer's instructions (QIAamp Fast DNA Stool Mini Kit #50951604) as described (Singh et al, 2020).…”

“…We recently uncovered a fitness advantage associated with loss of GGTA1 function in mice, which acts independently of αGal-specific immunity (Singh et al, 2020). Namely, the loss of αGal from the immunoglobulin (Ig)G-associated glycan structures increases IgG effector function (Singh et al, 2020) and resistance to bacterial sepsis, a life-threatening organ dysfunction caused by a deregulated response to infection (Singer et al, 2016), that accounts for 20% of global human mortality (Rudd et al, 2020).…”