Adaptation to Host-Specific Bacterial Pathogens Drives Rapid Evolution of a Human Innate Immune Receptor

Abstract

Graphical AbstractHighlights d The CEACAM3 gene appears recently in higher primates d It functions as a pathogen receptor and is one of the fastestevolving human genes d Human and chimp, but not gorilla or rhesus monkey, CEACAM3 binds human pathogens d CEACAM3 polymorphisms allow recognition of a broader set of bacterial pathogens SUMMARYThe selective pressure by infectious agents is a major driving force in the evolution of humans and other mammals. Members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family serve as receptors for bacterial pathogens of the genera Haemophilus, Helicobacter, Neisseria, and Moraxella, which engage CEACAMs via distinct surface adhesins. While microbial attachment to epithelial CEACAMs facilitates host colonization, recognition by CEACAM3, a phagocytic receptor expressed by granulocytes, eliminates CEACAMbinding bacteria. Sequence analysis of primate CEACAM3 orthologs reveals that this innate immune receptor is one of the most rapidly evolving human proteins. In particular, the pathogen-binding extracellular domain of CEACAM3 shows a high degree of non-synonymous versus synonymous nucleotide exchanges, indicating an exceptionally strong positive selection. Using CEACAM3 domains derived from different primates, we find that the amino acid alterations found in CEACAM3 translate into characteristic binding patterns for bacterial adhesins. One such amino acid residue is F62 in human and chimp CEACAM3, which is not present in other primates and which is critical for binding the OMP P1 adhesin of Haemophilus aegyptius. Incorporation of the F62containing motif into gorilla CEACAM3 results in a gain-of-function phenotype with regard to phagocytosis of H. aegyptius. Moreover, CEACAM3 polymorphisms found in human subpopulations widen the spectrum of recognized bacterial adhesins, suggesting an ongoing multivariate selection acting on this innate immune receptor. The species-specific detection of diverse bacterial adhesins helps to explain the exceptionally fast evolution of CEACAM3 within the primate lineage and provides an example of Red Queen dynamics in the human genome.

Evolution: Decoy Receptors as Unique Weapons to Fight Pathogens

“…In this issue of Current Biology, Adrian et al [12] investigated the host side of this evolutionary arms race. CEACAM1 is known to be under selective pressure to avoid pathogen binding [13].…”

CEACAM3—A Prim(at)e Invention for Opsonin-Independent Phagocytosis of Bacteria

“…More specifically, a CEACAM3 ortholog could not be identified even in Old World primates, such as baboon or African green monkey, by homology searches based on the extracellular Ig V -like domain (92). Large-scale genome comparisons between closely related primate species have revealed a high degree of non-synonymous vs. synonymous nucleotide changes in ortholog genes of CEACAM family members (93,94). Interestingly, the bacterial receptors within the CEACAM family (CEACAM1, CEACAM3, CEA, and CEACAM6) show an exceptionally strong signature of positive selection, suggesting that they belong to the fastest-evolving human genes.…”

“…Though ITAM-sequence containing CEACAM-related genes have been described for various mammals (95-97), a CEACAM3 gene with its specific exon/intron structure and the characteristic ITAM-like sequence seems to occur only after the emergence of Old World monkeys (around 35 million years ago) (98). Indeed, a CEACAM3 ortholog has only been detected at the syntenic locus in the genomes of baboon, macaque, orangutan, gorilla, chimpanzee, and humans (94). Due to uncertainties in the assembly of some genomes such as tarsier, lemurs, and lories, gene synteny is not a valid criterion to rule out the existence of CEACAM3 orthologs in lower primates.…”

“…In fact, while people outside of Africa mainly express the common CEACAM3 allele, particular ethnic groups harbor CEACAM3 variants. For example, in several groups with African ancestry, a third of the population expresses a distinct CEACAM3 allele (minor CEACAM3 allele) (94). This minor allele carries four non-synonymous single-nucleotide changes, which convert the CEACAM3-Ig V domain amino acid sequence into a near replica of the CEACAM1 Ig V domain.…”

“…This minor allele carries four non-synonymous single-nucleotide changes, which convert the CEACAM3-Ig V domain amino acid sequence into a near replica of the CEACAM1 Ig V domain. Modeling of the polymorphic CEACAM3 Ig V domain according to the known CEACAM3 crystal structure (7) reveals that these residues are surface exposed and three of the modified amino acids contribute to the CEACAM3 binding interface for various bacterial adhesins (94). It comes as no surprise that this minor CEACAM3 allele, which now mimics CEACAM1, shows a striking gain of function in that it recognizes additional bacterial adhesins, such as the OMP P1 protein of H. influenzae, which escape detection by the common CEACAM3 allele (94).…”