The adenylate cyclase toxin of Bordetella pertussis binds to target cells via the alpha(M)beta(2) integrin (CD11b/CD18)

The adenylate cyclase toxin (CyaA) of Bordetella pertussis is a major virul ence factor required for the early phases of lung colonization. It can inva de eukaryotic cells where, upon activation by endogenouse calmodulin, it ca talyzes the formation of unregulated cAMP levels. CyaA intoxication leads t o evident toxic effects on macrophages and neutrophils. Here, we demonstrat e that CyaA uses the alpha (M)beta (2) integrin (CD11b/CD18) as a cell rece ptor. Indeed, the saturable binding of CyaA to the surface of various hemat opoietic cell lines correlated with the presence of the alpha (M)beta (2) i ntegrin on these cells. Moreover, binding of CyaA to various murine cell li nes and human neutrophils was specifically blocked by anti-CD11b monoclonal antibodies. The increase of intracellular cAMP level and cell death trigge red by CyaA intoxication was also specifically blocked by anti-CD11b monocl onal antibodies. In addition, CyaA bound efficiently and triggered intracel lular cAMP increase and cell death in Chinese hamster ovary cells transfect ed with alpha (M)beta (2) (CD11b/CD18) but not in cells transfected with th e vector alone or with the alpha (X)beta (2) (CD11c/CD18) integrin. Thus, t he cellular distribution of CD11b, mostly on neutrophils, macrophages, and dendritic and natural killer cells, supports a role for CyaA in disrupting the early, innate antibacterial immune response.