Contribution of pertussis toxin (PT) and adenylate cyclase toxin (ACT) to pathogenicity of Bordetella pertussis.

The adenylate cyclase (AC)-affecting toxins of B. pertussis contribute to disease progression via: (A) PT is endocytosed into a cell and, following intracellular processing by the endoplasmic reticulum, the alpha subunit is released into the cytosol. This subunit ADP-ribosylates the alpha subunit of G proteins, disassociating it from its G protein coupled receptor (GPCR) on the cell surface inhibiting recruitment of immune cells to the site of infection. (B) ACT interacts with cell surface complement receptor (CR3) on macrophages and neutrophils, affecting antigen presentation and recruitment of the downstream adaptive immune response. The AC domain translocates to the cell cytoplasm and is stimulated upon calmodulin binding, leading to increased cAMP levels, inhibiting pro-inflammatory cytokine release and complementing mediated phagocytosis, and interfering with immune cell recruitment. (C) PT released into the bloodstream from cells growing on ciliated epithelial lung cells has been shown to contribute to development of leukocytosis. The mechanism is unclear but several have been proposed including (C1) PT inhibiting migration of lymphocytes across epithelium layers, (C2) PT interfering with GPCR signalling, effecting immune cell recruitment, (C3) PT inhibiting GPCRs required for leukocytes to stick to lymph nodes, interfering with extravasation, and (C4) PT stimulating the expansion of normal naïve immune cells and not proliferation of activated cells. (D) ACT inhibits biofilm formation by interfering with filamentous haemagglutinin–filamentous haemagglutinin (FHA-FHA) interactions between cells. The AC domain of the toxin binds to the mature C-terminal domain (MCD) at the distal tip of the FHA protein, blocking its function in biofilm.