Pneumolysin Causes Neuronal Cell Death through Mitochondrial Damage

Abstract

Bacterial toxins such as pneumolysin are key mediators of cytotoxicity in infections. Pneumolysin is a pore-forming toxin released by Streptococcus pneumoniae, the major cause of bacterial meningitis. We found that pneumolysin is the pneumococcal factor that accounts for the cell death pathways induced by live bacteria in primary neurons. The pore-forming activity of pneumolysin is essential for the induction of mitochondrial damage and apoptosis. Pneumolysin colocalized with mitochondrial membranes, altered the mitochondrial membrane potential, and caused the release of apoptosis-inducing factor and cell death. Pneumolysin induced neuronal apoptosis without activating caspase-1, -3, or -8. Wild-type pneumococci also induced apoptosis without activation of caspase-3, whereas pneumolysin-negative pneumococci activated caspase-3 through the release of bacterial hydrogen peroxide. Pneumolysin caused upregulation of X-chromosome-linked inhibitor of apoptosis protein and inhibited staurosporine-induced caspase activation, suggesting the presence of actively suppressive mechanisms on caspases. In conclusion, our results indicate additional functions of pneumolysin as a mitochondrial toxin and as a determinant of caspase-independent apoptosis. Considering this, blocking of pneumolysin may be a promising cytoprotective strategy in pneumococcal meningitis and other infections.

Radical scavenging, prolyl endopeptidase inhibitory, and antimicrobial potential of a cultured Himalayan lichenCetrelia olivetorum

“…A pneumococcal exotoxin (ExoY) has been reported for its potential to cause endothelial Tau hyperphosphorylation (Ochoa et al, 2012). While reports related to direct role of ExoY in the onset of AD are lacking, there are reports regarding bacterial and viral involvement in the pathogenesis of neurodegeneration (Braun et al, 2007;Chiara et al, 2012;Nicolson & Haier, 2009). Pseudomonas aeruginosa is known to be an opportunistic human pathogen that causes microbial infection in immunocompromised condition, especially in old age (Gellatly & Hancock, 2013).…”

“…The study indicates therapeutic potential of Himalayan lichen C. olivetorum against neurodegenerative diseases, encourages its commercial exploitation through mass culture and suggests further research on purification of bioactive components responsible for the observed biological activities. Furthermore, it has also been reported that herpes simplex virus (HSV-1) has considerable involvement in neuronal damage (Braun et al, 2007;Chiara et al, 2012), hence antiviral potential of bioactive components should also be analyzed.…”

Pathogenic and opportunistic respiratory bacteria-induced apoptosis

“…In macrophages there exists a low-level of apoptosis following exposure to non-opsonised largely extracellular bacteria [54]. Still, the production hydrogen peroxide by the pneumococcus induces cell death in neurons, microglia and brain microvascular endothelial cells [21,[58][59][60] also studied a variety of other pneumococcal factors in the induction of microglial apoptosis and found no role for choline binding protein A, autolysin, surface IgA protease, zinc metalloprotease, pneumococcal surface antigen A or the comA gene involved in DNA transformation [60]. In monocyte-derived macrophages autolysin, neuraminidase or hyaluronidase did not influence apoptosis induction [54].…”

“…Pneumolysin activates the innate immune system through Toll-like receptor 4 (TLR4) [53] and described as induced neuronal apoptosis without activating caspase-1, -3, or -8. However, the pneumolysin functions as a mitochondrial toxin is considered as a determinant of caspase-independent apoptosis [21].…”

“…Recently, two strong candidates for the LOS signaling protein have been identified in myeloid cells and have been termed Toll-like receptor-2 and 4 (TLR2 and TLR4) [20]. TLR2 is involved in the [21], and bacterial products such as lipopeptides [22]. As for TLR4, it has been shown to mediate the effect of Gram-negative bacteria by LPS [23] together with CD14 [24].…”