Fig 1.
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.
Fig 2.
The host cell membrane attacking toxins of Staphylococcus aureus and their roles beyond host cell lysis.
(A) Phagocytosis of invading bacteria is followed by fusing of the phagosome to the lysosome, resulting in destruction of the bacteria. S. aureus alpha (α) and phenol-soluble modulin (PSM) toxins inhibit fusing of the lysosome. This enables the bacteria to escape from the phagosome into the cytoplasm, allowing intracellular niche establishment and replication. (B) PSM toxins target cohabiting bacterial species within established niches, aiding in competition for resources and competitive exclusion of nonkin isolates. (C) PSM toxins have surfactant properties in vitro, enabling sliding movement across agar surfaces in the absence of traditional mobility structures such as flagella and pili. (D) Pore-forming toxins are involved at each step of S. aureus biofilm formation. During the initial cell attachment phase, alpha-toxin is involved in establishing cell-to-cell contacts, enabling the formation of secondary biofilm structures. In the later stages of the biofilm lifestyle, extracellular matrices develop, surrounding the cells within the biofilm. In the presence of extracellular DNA (eDNA), beta-toxin covalently cross-links with itself, adding to this extracellular nucleoprotein biofilm matrix and contributing to the formation of complex biofilm secondary structuring. Detachment from the mature biofilm allows for dispersal to new sites of infection. PSM toxins are involved in this stage of the biofilm lifestyle, aiding release of cell clusters from the main body of the biofilm.