Phagocytosis, Innate Immunity, and Host–Pathogen Specificity

In mammals, phagocytosis is essential for a variety of biological events, including tissue remodeling and the continuous clearance of dying cells. Furthermore, phagocytosis represents an early and crucial event in triggering host defenses against invading pathogens, which is the focus of this commentary. Phagocytosis comprises a series of events, starting with the binding and recognition of particles by cell surface receptors, followed by the formation of actin-rich membrane extensions around the particle. Fusion of the membrane extensions results in phagosome formation, which precedes phagosome mat-uration into a phagolysosome. Pathogens inside the phagoly-sosome are destroyed by lowered pH, hydrolysis, and radical attack. As a result of this process, pathogen-derived molecules can be presented at the cell surface (antigen presentation), allowing the induction of acquired immunity (1). These early events that are mediated by the innate immune system are critical for host survival. Here we discuss new insights into how broad classes of microbial substructures are recognized by molecules of the innate immune system that are shared by many species, and the interspecies receptor diversity that has evolved to match distinct species-specific environmental challenges. CEACAM3: A Phagocytic Receptor in Man. Human beings are the only reservoir for Neisseria meningitidis and N. gonorrhoeae , Haemophilus influenza , and Moraxella catarrhalis. In this issue, Schmitter et al. (2) describe the elegant manner by which the human immune system recognizes these highly adapted species of commensal Gram-negative bacteria via a unique surface receptor known as carcinoembryonic antigen–related cell adhesion molecule 3 (CEACAM3, also known as CD66d). CEACAM3, a member of the CD66 family of receptors, which is now the subject of intense scrutiny, not only binds these uniquely human bacteria but mediates bacterial internalization (3, 4) via a signal trans-duction pathway that involves the small GTPase, Rac. CEACAM3 is a single chain molecule that is expressed exclusively on granulocytes and appears to function specifically in the phagocytosis of commensal bacteria and the associated signal transduction events driven by these bacteria. Unlike the Toll receptor family of innate immune receptors, which has ancient orthologs in flies and other primitive organisms, CEACAM3 has no homologue in rodents and nonhuman primates, matching the species-specificity of N. gonorrhoeae , H. influenza , and M. catarrhalis. In the case of N. gonorrhoeae , CEACAM3 interacts with the 11-membered opacity (OPA) protein family. Accordingly, Schmitter et al. suggest CEACAM3 to be a phagocytic receptor for the bacterial surface proteins P5 of …