Evasion of human innate and acquired immunity by a bacterial homolog of CD11b that inhibits opsonophagocytosis

Microbial pathogens must evade the human immune system to survive, dissemin ate and cause disease. By proteome analysis of the bacterium Group A Strept ococcus (GAS), we identified a secreted protein with homology to the alpha -subunit of Mac-1, a leukocyte beta (2) integrin required for innate immuni ty to invading microbes. The GAS Mac-1-like protein (Mac) was secreted by m ost pathogenic strains, produced in log-phase and controlled by the covR-co vS two-component gene regulatory system, which also regulates transcription of other GAS virulence factors. Patients with GAS infection had titers of antibody specific to Mac that correlated with the course of disease, demons trating that Mac was produced in vivo. Mac bound to CD16 (Fc gamma RIIIB) o n the surface of human polymorphonuclear leukocytes and inhibited opsonopha gocytosis and production of reactive oxygen species, which resulted in sign ificantly decreased pathogen killing. Thus, by mimicking a host-cell recept or required for an innate immune response, the GAS Mac protein inhibits pro fessional phagocyte function by a novel strategy that enhances pathogen sur vival, establishment of infection and dissemination.