Humans and chimpanzees are more sensitive to endotoxin than are 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. CMP–N-acetylneuraminic acid hydroxylase (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 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 reintroduction of Neu5Gc into Cmah−/− macrophages suppressed these differences. Cmah−/− mice also showed enhanced bacterial clearance during sublethal lung infection. Although monocytes and monocyte-derived macrophages from humans and chimpanzees exhibited marginal differences in LPS responses, human monocyte-derived macrophages killed Escherichia coli and ingested E. coli BioParticles better. Metabolic reintroduction of Neu5Gc into human macrophages suppressed these differences. Although 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 sublethal 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.
This work was supported by National Institutes of Health Grants R01GM32373 (to A.V.) and R01AR060949 (to P.T.M.), as well as by the Mathers Foundation of New York. Blood samples from chimpanzees were provided by the Yerkes Primate Center (Atlanta, GA) under National Institutes of Health Base Grant ORIP/OD P51OD011132.
The online version of this article contains supplemental material.
- Received August 24, 2016.
- Accepted January 4, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.