Neisserial porin (PorB) causes rapid calcium influx in target cells and induces apoptosis by the activation of cysteine proteases

Abstract

The porin (PorB) of Neisseria gonorrhoeae is an intriguing bacterial factor owing to its ability to translocate from the outer bacterial membrane into host cell membranes where it modulates the infection process. Here we report on the induction of programmed cell death after prolonged infection of epithelial cells with pathogenic Neisseria species. The underlying mechanism we propose includes translocation of the porin, a transient increase in cytosolic Ca 2⍣ and subsequent activation of the Ca 2⍣ dependent protease calpain as well as proteases of the caspase family. Blocking the porin channel by ATP eliminates the Ca 2⍣ signal and also abolishes its pro-apoptotic function. The neisserial porins share structural and functional homologies with the mitochondrial voltage-dependent anion channels (VDAC). The neisserial porin may be an analogue or precursor of the ancient permeability transition pore, the putative central regulator of apoptosis.

Gene Expression Pattern in Human Brain Endothelial Cells in Response to Neisseria meningitidis

“…Since array data revealed up-regulation of proapoptotic genes and at the same time down-regulation of antiapoptotic genes in HBMEC, we next determined whether incubation with N. meningitidis leads to apoptosis in cultured HBMEC. There are conflicting reports in the literature regarding apoptosis induction by N. meningitidis (8,33,34,39,40). We selected different assays that cover a range of apoptotic events in human cells.…”

“…Two groups of investigators have analyzed in detail the induction of apoptosis by pathogenic neisseriae in HeLa cells. Müller and coworkers postulated that apoptosis is induced in HeLa cells by either a native or recombinant gonococcal porin, PIB, or intact gonococci (39,40). Massari and coworkers demonstrated that purified PorB from N. meningitidis or PorB from live bacteria associated with mitochondria prevents apoptosis (34).…”

Channels formed by subnanomolar concentrations of the toxin aerolysin trigger apoptosis of T lymphomas

“…This would give the bacteria a potential advantage by reducing the likelihood of necrosis and avoiding a localized in¯ammatory response. At least two other channel-forming toxins, Staphylococcus aureus alpha toxin and Actinobacillus actinomycetemcomitans leukotoxin (Chen and Zychlinsky, 1994), also cause apoptosis at low concentrations, and it has been shown recently that, like aerolysin, the outer membrane porin PorB of Neisseria gonorrhoeae causes rapid calcium in¯ux into epithelial cells, which may induce apoptosis by activating cysteine proteases (Muller et al, 1999). It seems reasonable to suppose that the vacuolation of BHK endoplasmic reticulum by aerolysin, which was reported by Abrami et al (1998b), was also a consequence of apoptosis, as was the G-protein activation the same group reported in granulocytes (Krause et al, 1998).…”

Structural basis for solute transport, nucleotide regulation, and immunological recognition of Neisseria meningitidis PorB

“…In addition, PorB directly interacts with the host mitochondrial voltage-dependent anion channel (VDAC) (7). Importantly, the insertion of PorB into mitochondrial membranes is known to influence apoptosis (7)(8)(9)(11)(12)(13). Because both the mitochondrial membrane potential and VDAC are important for apoptosis (14), PorB may influence the initiation of apoptosis at multiple checkpoints.…”