Loss of CMAH during Human Evolution Primed the Monocyte–Macrophage Lineage toward a More Inflammatory and Phagocytic State

Abstract

Humans and chimpanzees are more sensitive to endotoxin than mice or monkeys, but any underlying differences in inflammatory physiology have not been fully described or understood. We studied innate immune responses in Cmah−/− mice, emulating human loss of the gene encoding production of Neu5Gc, a major cell surface sialic acid. CMAH loss occurred ~2-3 million years ago, after the common ancestor of humans and chimpanzees, perhaps contributing to speciation of the genus Homo. Cmah−/− mice manifested a decreased survival in endotoxemia following bacterial lipopolysaccharide (LPS) injection. Macrophages from Cmah−/− mice secreted more inflammatory cytokines with LPS-stimulation and showed more phagocytic activity. Macrophages and whole blood from Cmah−/− mice also killed bacteria more effectively. Metabolic re-introduction of Neu5Gc into Cmah−/− macrophages suppressed these differences. Cmah−/− mice also showed enhanced bacterial clearance during sub-lethal lung infection. Although monocytes and monocyte-derived macrophages from humans and chimpanzees exhibited marginal differences in LPS responses, human monocyte-derived macrophages killed E. coli and ingested E. coli bioparticles better. Metabolic re-introduction of Neu5Gc into human macrophages suppressed these differences. While multiple mechanisms are likely involved, one cause is altered expression of C/EBPβ, a transcription factor affecting macrophage function. Loss of Neu5Gc in Homo likely had complex effects on immunity, providing greater capabilities to clear sub-lethal bacterial challenges, possibly at the cost of endotoxic shock risk. This trade-off may have provided a selective advantage when Homo transitioned to butchery using stone tools. The findings may also explain why the Cmah−/− state alters severity in mouse models of human disease.

Streptococcus pneumoniae evades host cell phagocytosis and limits host mortality through its cell wall anchoring protein PfbA

“…Mouse infection assays were performed as previously described (17, 33, 44, 45). For the lung infection model, CD-1 mice (Slc:ICR, 8 weeks, female) were infected intratracheally with 4.3-6.7 × 10 6 CFUs of S. pneumoniae.…”

Biochemical, Cellular, Physiological, and Pathological Consequences of Human Loss of N‐Glycolylneuraminic Acid

“…Therefore, a Cmah ‐null mouse ( Cmah −/− ) with the human‐like exon deletion was generated to provide a practical model for studying the immediate loss of CMAH as it would have happened in hominins ≈3 Ma. Cmah −/− mice have several human‐like phenotypes (Table ), including the induction of anti‐Neu5Gc antibodies, enhancement of cancer inflammation and progression of Neu5Gc containing tumors, enhanced immune clearance of recombinant Neu5Gc containing therapeutics, delayed skin wound healing, enhanced age‐related hearing loss, altered immune responses, sexual selection through Neu5Gc antigenicity, altered susceptibility to metabolic disorders, altered susceptibility to muscular dystrophy, and a xeno‐antibody response against the vascular endothelium after nutritional incorporation of Neu5Gc …”

“…This work, along with evidence that feeding Neu5Gc to primary human T cells suppresses their cell proliferation after activation, suggests that independent of CMAH oxidoreductase activity, metabolic incorporation of Neu5Gc from exogenous sources can affect some cell‐signaling processes. More recently, Neu5Gc feeding has been found to suppress bacterial killing by macrophages from Cmah −/− mice and humans, where the expression of the transcription factor C/EBPβ was also suppressed . Further studies are needed to systematically elucidate the possible mechanisms contributing to the observed phenotypes (Table ).…”

“…As most microbial sialidases have a preference for Neu5Ac or Neu5Gc and host NEU1 prefers α2–8‐linked Neu5Ac over Neu5Gc, it could be that NEU1 has a preference for the α2–3 or α2–6 Neu5Ac versus Neu5Gc sialic acid linkages commonly found on all host cell surfaces. If there is indeed a difference, this could potentially contribute towards the differences in signaling observed when feeding Neu5Gc in vitro …”

“…A small increase in the sensitivity of Cmah −/− mice to endotoxin ex vivo was also observed, with a more profound effect in vivo. We further investigated a functional ramification of hyperinflammation (bacterial killing) and found that both Cmah −/− mice and humans exhibited a greater capability to kill nonpathogenic bacteria than their WT and chimpanzee counterparts . Thus, it can be speculated that human CMAH loss might have been beneficial for clearing minor infections, but could be potentially deleterious in severe infection and endotoxic shock.…”