Differential Modulation of TNF-α–Induced Apoptosis by Neisseria meningitidis

Abstract

Infections by Neisseria meningitidis show duality between frequent asymptomatic carriage and occasional life-threatening disease. Bacterial and host factors involved in this balance are not fully understood. Cytopathic effects and cell damage may prelude to pathogenesis of isolates belonging to hyper-invasive lineages. We aimed to analyze cell–bacteria interactions using both pathogenic and carriage meningococcal isolates. Several pathogenic isolates of the ST-11 clonal complex and carriage isolates were used to infect human epithelial cells. Cytopathic effect was determined and apoptosis was scored using several methods (FITC-Annexin V staining followed by FACS analysis, caspase assays and DNA fragmentation). Only pathogenic isolates were able to induce apoptosis in human epithelial cells, mainly by lipooligosaccharide (endotoxin). Bioactive TNF-α is only detected when cells were infected by pathogenic isolates. At the opposite, carriage isolates seem to provoke shedding of the TNF-α receptor I (TNF-RI) from the surface that protect cells from apoptosis by chelating TNF-α. Ability to induce apoptosis and inflammation may represent major traits in the pathogenesis of N. meningitidis. However, our data strongly suggest that carriage isolates of meningococci reduce inflammatory response and apoptosis induction, resulting in the protection of their ecological niche at the human nasopharynx.

Meningococcal Porin PorB Prevents Cellular Apoptosis in a Toll-Like Receptor 2- and NF-κB-Independent Manner

“…Some examples of bacteria that inhibit apoptosis are Chlamydia (20,22,79), Shigella flexneri (11), Brucella (28), Porphyromonas gingivalis (56,58), Neisseria meningitidis, and Neisseria gonorrhoeae (4,23,31,42,50,55,62,65,73). Our group and other workers have reported that live N. meningitidis and purified meningococcal porin inhibit apoptosis (15,49,50,62,75), potentially via multiple mechanisms. While meningococcal infection induces NF-B-mediated upregulation of antiapoptotic genes, purified PorB and PorB from live bacteria directly interact with mitochondria and modulate their membrane potential, preventing release of cytochrome c. N. gonorrhoeae and purified gonococcal porin PIB induce NF-B-mediated upregulation of antiapoptotic genes (4,5,23,33,55,65), which could also contribute to prevention of apoptosis.…”

Neisseria gonorrhoeae-Mediated Inhibition of Apoptotic Signalling in Polymorphonuclear Leukocytes

“…We also show that PMNs can be a significant source of proinflammatory cytokines and chemokines during infection, in addition to the epithelial cells which are thought to be responsible for initial PMN recruitment. Numerous studies of epithelial cells and lymphocytes have shown both pro-and antiapoptotic effects of infection with both N. gonorrhoeae (6,27,36,39,40,50,51) and the closely related N. meningitidis (17,48). However, PMN apoptosis during N. gonorrhoeae infection has not been examined as extensively (68), and it has not been explored at all with N. meningitidis.…”

“…Gonococcal infection has also been shown to exert a delaying effect on spontaneous PMN apoptosis during ex vivo infection (68). While the mechanisms by which N. gonorrhoeae manipulates apoptotic signaling in epithelial cells and lymphocytes have been extensively studied (6,17,27,36,40,48,50,51), whether bacterial infection acts on the same signaling pathways in the context of PMNs is less well defined. Several other microorganisms have been shown to influence PMN survival in either a pro-or antiapoptotic manner; in particular, pathogens such as Anaplasma phagocytophilum and Chlamydia trachomatis, which reside and replicate within PMNs, have evolved mechanisms to actively delay PMN apoptosis in order to allow sufficient time to complete their replicative cycles (29,71).…”

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

“…The TNFR1 ectodomains released in the extracellular space chelate sTNF-α, providing negative feedback to the TNF-α-induced inflammatory loop (13). Pathogenic bacteria, including Chlamydia trachomatis, Neisseria meningitides, and Staphylococcus aureus, have evolved TNFR1 shedding mechanisms as a strategy for circumventing the host immune response (14)(15)(16).…”