Pneumococcal Hydrogen Peroxide–Induced Stress Signaling Regulates Inflammatory Genes

Loose, Maria; Hudel, Martina; Zimmer, Klaus Peter; Garcı́a, Ernesto; Hammerschmidt, Sven; Lucas, Rudolf; Chakraborty, Trinad; Pillich, Helena

doi:10.1093/infdis/jiu428

Cited by 32 publications

(34 citation statements)

References 47 publications

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“…However, it is possible that SpxB-dependent H 2 O 2 induces stress within epithelial cells that may lead to alternative, non-cytolytic death processes. For instance, it has been shown that SpxB-induced H 2 O 2 triggers genotoxicity and conserved stress responses within the epithelium [24, 36]. …”

Section: Discussionmentioning

confidence: 99%

Pyruvate oxidase of Streptococcus pneumoniae contributes to pneumolysin release

et al. 2016

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Background Streptococcus pneumoniae is one of the leading causes of community acquired pneumonia and acute otitis media. Certain aspects of S. pneumoniae’s virulence are dependent upon expression and release of the protein toxin pneumolysin (PLY) and upon the activity of the peroxide-producing enzyme, pyruvate oxidase (SpxB). We investigated the possible synergy of these two proteins and identified that release of PLY is enhanced by expression of SpxB prior to stationary phase growth.ResultsMutants lacking the spxB gene were defective in PLY release and complementation of spxB restored PLY release. This was demonstrated by cytotoxic effects of sterile filtered supernatants upon epithelial cells and red blood cells. Additionally, peroxide production appeared to contribute to the mechanism of PLY release since a significant correlation was found between peroxide production and PLY release among a panel of clinical isolates. Exogenous addition of H2O2 failed to induce PLY release and catalase supplementation prevented PLY release in some strains, indicating peroxide may exert its effect intracellularly or in a strain-dependent manner. SpxB expression did not trigger bacterial cell death or LytA-dependent autolysis, but did predispose cells to deoxycholate lysis.ConclusionsHere we demonstrate a novel link between spxB expression and PLY release. These findings link liberation of PLY toxin to oxygen availability and pneumococcal metabolism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-016-0881-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Pyruvate oxidase of Streptococcus pneumoniae contributes to pneumolysin release

et al. 2016

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“…In order to restore ER homeostasis, the cell activates the UPR, leading to a decreased cap-dependent protein synthesis and an increased expression of chaperones. Several pulmonary diseases have been described to induce ER stress in epithelial cells [30,31,32]. Specifically, various chronic pulmonary diseases that are linked to chronic inflammation, including asthma, COPD, or CF, have been associated with ER stress in airway epithelium [33].…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress Is a Danger Signal Promoting Innate Inflammatory Responses in Bronchial Epithelial Cells

Mijošek

Lasitschka²,

Warth³

et al. 2016

J Innate Immun

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Endoplasmic reticulum (ER) stress is associated with chronic pulmonary inflammatory diseases. We hypothesized that the combined activation of both Toll-like receptor (TLR) signaling and ER stress might increase inflammatory reactions in otherwise tolerant airway epithelial cells. Indeed, ER stress resulted in an increased response of BEAS-2B and human primary bronchial epithelial cells to pathogen-associated molecular pattern stimulation with respect to IL6 and IL8 production. ER stress elevated p38 and ERK MAP kinase activation, and pharmacological inhibition of these kinases could inhibit the boosting effect. Knockdown of unfolded protein response signaling indicated that mainly PERK and ATF6 were responsible for the synergistic activity. Specifically, PERK and ATF6 mediated increased MAPK activation, which is needed for effective cytokine secretion. We conclude that within airway epithelial cells the combined activation of TLR signaling and ER stress-mediated MAPK activation results in synergistic proinflammatory activity. We speculate that ER stress, present in various chronic pulmonary diseases, boosts TLR signaling and therefore proinflammatory cytokine production, thus acting as a costimulatory danger signal.

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“…The H 2 O 2 enables bacteria to escape from macrophage phagocytosis and thus contributes to the onset of bacteremia and infectious endocarditis. Regarding S. pneumoniae, several investigations revealed that the H 2 O 2 produced by S. pneumoniae is one of the virulence factors of this species (17)(18)(19)(20)(21). H 2 O 2 contributes to pneumococcal lung and blood infections in experimental animals (17,19).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the H 2 O 2 produced by S. pneumoniae is a cytotoxic virulence factor (17)(18)(19)(20)(21). A recent study showed that pneumococcal H 2 O 2 induces the activation of stress-related cellular signaling pathways (21). We also found that streptococcal H 2 O 2 stimulates the production of cytokines, such as tumor necrosis factor alpha and interleukin-6 (15,22).…”

mentioning

confidence: 85%

“…The cytotoxic effects of streptococcal H 2 O 2 on THP-1 macrophages were also observed with S. sanguinis (15,16), suggesting that H 2 O 2 contributes to the pathogenicity of the mitis group of streptococci. In fact, the H 2 O 2 produced by S. pneumoniae is a cytotoxic virulence factor (17)(18)(19)(20)(21). A recent study showed that pneumococcal H 2 O 2 induces the activation of stress-related cellular signaling pathways (21).…”

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Streptococcus oralis Induces Lysosomal Impairment of Macrophages via Bacterial Hydrogen Peroxide

et al. 2016

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c Streptococcus oralis, an oral commensal, belongs to the mitis group of streptococci and occasionally causes opportunistic infections, such as bacterial endocarditis and bacteremia. Recently, we found that the hydrogen peroxide (H 2 O 2 ) produced by S. oralis is sufficient to kill human monocytes and epithelial cells, implying that streptococcal H 2 O 2 is a cytotoxin. In the present study, we investigated whether streptococcal H 2 O 2 impacts lysosomes, organelles of the intracellular digestive system, in relation to cell death. S. oralis infection induced the death of RAW 264 macrophages in an H 2 O 2 -dependent manner, which was exemplified by the fact that exogenous H 2 O 2 also induced cell death. Infection with either a mutant lacking spxB, which encodes pyruvate oxidase responsible for H 2 O 2 production, or Streptococcus mutans, which does not produce H 2 O 2 , showed less cytotoxicity. Visualization of lysosomes with LysoTracker revealed lysosome deacidification after infection with S. oralis or exposure to H 2 O 2 , which was corroborated by acridine orange staining. Similarly, fluorescent labeling of lysosome-associated membrane protein-1 gradually disappeared during infection with S. oralis or exposure to H 2 O 2 . The deacidification and the following induction of cell death were inhibited by chelating iron in lysosomes. Moreover, fluorescent staining of cathepsin B indicated lysosomal destruction. However, treatment of infected cells with a specific inhibitor of cathepsin B had negligible effects on cell death; instead, it suppressed the detachment of dead cells from the culture plates. These results suggest that streptococcal H 2 O 2 induces cell death with lysosomal destruction and then the released lysosomal cathepsins contribute to the detachment of the dead cells. Streptococcus oralis, a commensal bacterium in the oral cavity, belongs to the group of oral inhabitants of the mitis group of streptococci (1-4). Members of this group, including Streptococcus sanguinis and Streptococcus gordonii, are dominant colonizers of human teeth and are involved in dental plaque formation (1-3). Pathogenic streptococcal species, such as Streptococcus pneumoniae and Streptococcus mitis, are also members of the mitis group (2, 4-6). This group has been implicated as a possible cause of human cardiovascular diseases, including infective endocarditis and atherosclerosis. S. oralis is frequently isolated from cases of infective endocarditis (7-10), and ribosomal DNAs of the mitis group were detected in atheromatous plaque (11). The rate of bacteremia caused by members of the mitis group of streptococci is comparable to that caused by group A or B streptococci (12).The members of the mitis group of streptococci produce hydrogen peroxide (H 2 O 2 ) (2, 13, 14), which is important in bacterial competition in microbial communities, such as oral biofilms (13,14). S. sanguinis and S. gordonii produce H 2 O 2 in quantities sufficient to reduce the growth of many oral bacteria, including the cariogenic bacterium Strepto...

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Pneumococcal Hydrogen Peroxide–Induced Stress Signaling Regulates Inflammatory Genes

Cited by 32 publications

References 47 publications

Pyruvate oxidase of Streptococcus pneumoniae contributes to pneumolysin release

Pyruvate oxidase of Streptococcus pneumoniae contributes to pneumolysin release

Endoplasmic Reticulum Stress Is a Danger Signal Promoting Innate Inflammatory Responses in Bronchial Epithelial Cells

Streptococcus oralis Induces Lysosomal Impairment of Macrophages via Bacterial Hydrogen Peroxide

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