Grant: Project Grant

The carcinoembryonic antigen-related family of cellular adhesion molecules (CEACAMs) mediate intercellular binding-dependent control of cellular growth and differentiation in vertebrates. The abundant expression of CEACAMs on epithelial cells that line mucosal surfaces has led it to become a target for a wide variety of disease-causing microbes, including those that cause respiratory, gastrointestinal and genital infections. Beyond its function in the maintenance of epithelia, CEACAM1 is present on most immune cells, and is presumed to function in turning down immune signaling once the activation is sufficient. We and others have shown that bacterial binding to CEACAM1 on these immune cells inhibits their response to a variety of stimuli. This effect is key to understand because two commercially-licensed vaccines, and others in development, include CEACAM-binding proteins, raising the question of whether their inclusion hampers the vaccine's ability to elicit protection. This proposal is based upon the hypothesis that Neisseria gonorrhoeae, the bacteria that causes sexually-transmitted gonorrhea, bind CEACAM1 to promote infection by suppressing the innate and adaptive response that mucosal infection would otherwise elicit. Bacterial binding to CEACAMs is host specific, restricting use of animal models. This program harnesses our success in developing a mouse line that expresses a chimeric CEACAM1 that combines the bacterial binding sequence of human CEACAM1 with the cell signaling components of native mouse CEACAM1. We will use these to dissect the effect of CEACAM1 binding on infection by and/or immunity against N. gonorrhoeae. Our findings will guide development of more effective vaccines and therapies that subvert CEACAM1 signaling to promote bacterial clearance and prevent disease.