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

Area of Science:

• Evolutionary biology
• Immunology
• Genomics

Background:

• Infectious agents are key drivers of mammalian evolution.
• CarcinOembryonic Antigen-related cell Adhesion Molecule (CEACAM) family members act as receptors for various bacterial pathogens.
• CEACAM3, an innate immune receptor on granulocytes, recognizes and eliminates CEACAM-binding bacteria.

Purpose of the Study:

• To investigate the rapid evolution of the primate CEACAM3 innate immune receptor.
• To understand how genetic alterations in CEACAM3 affect bacterial binding and phagocytosis.
• To explore the role of CEACAM3 in host-pathogen interactions and primate evolution.

Main Methods:

• Comparative sequence analysis of primate CEACAM3 orthologs.
• Assessment of nucleotide exchange rates to identify positive selection.
• Functional analysis of CEACAM3 domains to determine bacterial adhesin binding patterns.
• Site-directed mutagenesis to investigate the role of specific amino acid residues (e.g., F62).

Main Results:

• Primate CEACAM3 exhibits exceptionally rapid evolution, particularly in its extracellular domain, under strong positive selection.
• Amino acid variations in CEACAM3 correlate with distinct binding patterns for bacterial adhesins.
• The F62 residue in human and chimpanzee CEACAM3 is critical for binding Haemophilus aegyptius OMP P1 adhesin.
• Introducing the F62 motif into gorilla CEACAM3 confers enhanced phagocytosis of H. aegyptius.
• Human CEACAM3 polymorphisms expand the range of recognized bacterial adhesins.

Conclusions:

• Rapid evolution of CEACAM3 is driven by species-specific recognition of diverse bacterial adhesins.
• CEACAM3 exemplifies Red Queen dynamics, where host-pathogen co-evolution shapes the human genome.
• Ongoing selection on CEACAM3 contributes to its rapid evolutionary trajectory in primates.