Rapid evolution and bacterial evasion by a primate cell adhesion protein

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Proteins that interact with pathogens are among the most rapidly evolving in animal genomes, but how they can undergo such dramatic change while maintaining essential functions is a fundamental mystery. Carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family proteins have a wide range of adhesive, developmental and immunological roles at vertebrate epithelial surfaces. Besides important cellular functions, CEACAMs are targeted by bacterial ‘adhesin’ proteins to support host colonization. Contrary to their important ‘housekeeping’ functions, preliminary analyses suggest several CEACAMs are evolving rapidly in primates, particularly in the binding domain recognized by bacterial adhesins. This indicates pressure to avoid pathogen binding may accelerate CEACAM evolution. I hypothesize bacterial evasion drives CEACAM evolution in humans and related primates with consequences for pathogen immunity and host physiologic functions. This proposal will investigate the evolution and functional consequences of binding between primate CEACAM proteins and bacterial adhesins, using primate CEACAM1 and the pathogenic bacteria Helicobacter pylori as a model system. CEACAM1-HopQ binding promotes H. pylori infection and injection of the oncoprotein CagA into host cells, leading to gastric inflammation and cancer development. My preliminary experiments demonstrate that rapid evolution of CEACAM1 in primates controls H. pylori binding between species. Using phylogenetic and population genetic analyses to trace recent CEACAM evolution in humans and primates, Aim I will pinpoint evolutionary patterns and molecular determinants of adhesion recognition within host populations. Altered HopQ binding due to variation at identified residues will be measured in vitro with purified tagged- CEACAM1 variants and isogenic H. pylori strains carrying different HopQ alleles. Aim II will determine how HopQ and CEACAM1 variation impacts pathogenicity of H. pylori using cellular signals of binding to cells expressing CEACAM1 variants. This includes association of host cells with H. pylori, induction of proinflammatory cytokines and CagA phosphorylation. Aim III will assess homodimerization of CEACAM1 homologs and the ability of CEACAM1 variation to alter downstream regulatory signaling using interactions with natural killer cells or the induction of cytokines through CEACAM binding to chimeric protein constructs. This work will reveal how proteins can evolve to evade pathogens while maintaining essential ‘housekeeping’ functions. Results could ultimately inform treatment of H. pylori infections and screening and therapy for cancer and other genetic disorders. This work will be conducted at the University of Oregon under the guidance of my co-sponsors Dr.’s Barber and Guillemin. The research environment and training program provide copious chances for technical and professional development, including training in scientific communication through public presentation and publication of research, student mentorship and teaching, and application of Responsible Conduct in Research. This training program will provide excellent preparation for the establishment of an independent research program.