Two Distinct Mechanisms For Induction of Dendritic Cell Apoptosis in Response to Intact<i>Streptococcus pneumoniae</i>

Colino, Jesus; Snapper, Clifford M.

doi:10.4049/jimmunol.171.5.2354

Cited by 68 publications

(74 citation statements)

References 52 publications

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“…As demonstrated in another model, our experiments confirm that TLR2-dependent release of neurotoxins by microglia causes neuronal cell death (43). Additionally, initiation of TLR2-mediated and caspase-dependent cell death by pneumococcal cell wall has only been reported in TLR2-expressing cells such as endothelial cells or dendritic cells (41,44). Our finding of low TLR2-mRNA expression in resting astrocytes does not argue against an additional contribution of these cells in vivo because astrocytes have been shown to up-regulate TLR2 upon activation by bacterial compounds (45).…”

Section: Discussionsupporting

confidence: 65%

TLR2 Mediates Neuroinflammation and Neuronal Damage

Hoffmann¹,

Braun²,

Becker³

et al. 2007

The Journal of Immunology

128

108

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Innate immunity relies on pattern recognition receptors to detect the presence of infectious pathogens. In the case of Gram-positive bacteria, binding of bacterial lipopeptides to TLR2 is currently regarded as an important mechanism. In the present study, we used the synthetic bacterial lipopeptide Pam3CysSK4, a selective TLR2 agonist, to induce meningeal inflammation in rodents. In a 6-h rat model, intrathecal application of Pam3CysSK4 caused influx of leukocytes into the cerebrospinal fluid (CSF) and induced a marked increase of regional cerebral blood flow and intracranial pressure. In wild-type mice, we observed CSF pleocytosis and an increased number of apoptotic neurons in the dentate gyrus 24 h after intrathecal challenge. Inflammation and associated neuronal loss were absent in TLR2 knockout mice. In purified neurons, cytotoxicity of Pam3CysSK4 itself was not observed. Exposure of microglia to Pam3CysSK4 induced neurotoxic properties in the supernatant of wild-type, but not TLR2-deficient microglia. We conclude that TLR2-mediated signaling is sufficient to induce the host-dependent key features of acute bacterial meningitis. Therefore, synthetic lipopeptides are a highly specific tool to study mechanisms of TLR2-driven neurodegeneration in vivo.

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Section: Discussionsupporting

confidence: 65%

TLR2 Mediates Neuroinflammation and Neuronal Damage

Hoffmann¹,

Braun²,

Becker³

et al. 2007

The Journal of Immunology

128

108

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“…The present finding that IL-18 production induced by S. pneumoniae was dependent on TLR4 may account for the increased susceptibility to S. pneumoniae of mice that lack functional TLR4 (27). A previous report demonstrated that the interaction between PLY and TLR4 resulted in the induction of caspase-dependent host cell apoptosis in mice infected with S. pneumoniae (51), although several reports demonstrated that apoptosis-like cell death induced by S. pneumoniae or PLY in various types of cells is independent of caspases (6,10,12). In that report (51), it appeared that S. pneumoniae-induced apoptosis contributed to the host defense, because administration of the broad-spectrum caspase inhibitor z-VAD-fmk to mice increased the mortality rate after pneumococcal colonization in the nasopharynx.…”

Section: Discussionmentioning

confidence: 97%

Critical Involvement of Pneumolysin in Production of Interleukin-1α and Caspase-1-Dependent Cytokines in Infection withStreptococcus pneumoniaeIn Vitro: a Novel Function of Pneumolysin in Caspase-1 Activation

et al. 2008

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Pneumolysin is a pore-forming cytolysin known as a major virulence determinant of Streptococcus pneumoniae. This protein toxin has also been shown to activate the Toll-like receptor 4 (TLR4) signaling pathway. In this study, a mutant S. pneumoniae strain deficient in pneumolysin (⌬ply) and a recombinant pneumolysin protein (rPLY) were constructed. Upon infection of macrophages in vitro, the ability to induce the production of interleukin-1␣ (IL-1␣), IL-1␤, and IL-18 was severely impaired in the ⌬ply mutant, whereas there was no marked difference in the induction of tumor necrosis factor alpha (TNF-␣) and IL-12p40 between the wild type and the ⌬ply mutant of S. pneumoniae. When macrophages were stimulated with rPLY, the production of IL-1␣, IL-1␤, and IL-18 was strongly induced in a TLR4-dependent manner, whereas lipopolysaccharide, a canonical TLR4 agonist, hardly induced these cytokines. In contrast, lipopolysaccharide was more potent than rPLY in inducing the production of TNF-␣, IL-6, and IL-12p40, the cytokines requiring no caspase activation. Activation of caspase-1 was observed in macrophages stimulated with rPLY but not in those stimulated with lipopolysaccharide, and the level of activation was higher in macrophages infected with wild-type S. pneumoniae than in those infected with the ⌬ply mutant. These results clearly indicate that pneumolysin plays a key role in the host response to S. pneumoniae, particularly in the induction of caspase-1-dependent cytokines.

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“…Although induction of cell death is key to pathogenicity, the underlying mechanisms by which S. pneumoniae induces apoptosis (23)(24)(25) and necrosis (26) in host cells is not yet well understood. Although it is known that certain pneumococcal proteins elicit a potentially cytotoxic inflammatory response (4,27), here we asked whether S. pneumoniae or its secreted factors could directly generate DNA damage responses that could contribute to cell death. One such secreted factor could be hydrogen peroxide (H 2 O 2 ), produced by action of pyruvate oxidase (encoded by spxB) in S. pneumoniae (28), H 2 O 2 secreted by S. pneumoniae could potentially contribute to pneumococci-induced oxidative stress and elicit DNA damage response during infection.…”

Section: Significancementioning

confidence: 99%

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

Rai

Parrish

Tay

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

129

102

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Streptococcus pneumoniae is a leading cause of pneumonia and one of the most common causes of death globally. The impact of S. pneumoniae on host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show that S. pneumoniae induces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H 2 O 2 , plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H 2 O 2 , greatly suppresses S. pneumoniae-induced DNA damage and apoptosis. Importantly, S. pneumoniae induces DSBs in the lungs of animals with acute pneumonia, and H 2 O 2 production by S. pneumoniae in vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventing S. pneumoniaeinduced genotoxicity. Taken together, this study shows that S. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia.DNA damage | Streptococcus pneumoniae | hydrogen peroxide | γH2AX | Ku80

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Two Distinct Mechanisms For Induction of Dendritic Cell Apoptosis in Response to IntactStreptococcus pneumoniae

Cited by 68 publications

References 52 publications

TLR2 Mediates Neuroinflammation and Neuronal Damage

TLR2 Mediates Neuroinflammation and Neuronal Damage

Critical Involvement of Pneumolysin in Production of Interleukin-1α and Caspase-1-Dependent Cytokines in Infection withStreptococcus pneumoniaeIn Vitro: a Novel Function of Pneumolysin in Caspase-1 Activation

Streptococcus pneumoniaesecretes hydrogen peroxide leading to DNA damage and apoptosis in lung cells

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