Critical Involvement of Pneumolysin in Production of Interleukin-1α and Caspase-1-Dependent Cytokines in Infection with<i>Streptococcus pneumoniae</i>In Vitro: a Novel Function of Pneumolysin in Caspase-1 Activation

Shoma, Shereen; Tsuchiya, Kazuo; Kawamura, Ikuo; Nomura, Takeshi; Hara, Hideki; Uchiyama, Ryosuke; Daim, Sylvia; Mitsuyama, Masao

doi:10.1128/iai.01269-07

Cited by 70 publications

(60 citation statements)

References 58 publications

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“…In contrast, release of IL-1b protein was induced by wild-type S. pneumoniae but not by PLY-deficient pneumococci (Fig. 1B), as shown before in experiments with peritoneal macrophages (43). Similarly, IL-1b production depended on PLY expression also in human PBMCs and THP-1 monocytes when infected with the unencapsulated serotype 2 pneumococci R6x (Fig.…”

Section: Production Of Il-1b In S Pneumoniae-infected Cellsmentioning

confidence: 73%

The NLRP3 Inflammasome Is Differentially Activated by Pneumolysin Variants and Contributes to Host Defense in Pneumococcal Pneumonia

Witzenrath

Pache

Lorenz

et al. 2011

The Journal of Immunology

225

201

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Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, and sepsis. Pneumococci can be divided into >90 serotypes that show differences in the pathogenicity and invasiveness. We tested the hypotheses that the innate immune inflammasome pathway is involved in fighting pneumococcal pneumonia and that some invasive pneumococcal types are not recognized by this pathway. We show that human and murine mononuclear cells responded to S. pneumoniae expressing hemolytic pneumolysin by producing IL-1β. This IL-1β production depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Some serotype 1, serotype 8, and serotype 7F bacteria, which have previously been associated with increased invasiveness and with production of toxins with reduced hemolytic activity, or bacterial mutants lacking pneumolysin did not stimulate notable IL-1β production. We further found that NLRP3 was beneficial for mice during pneumonia caused by pneumococci expressing hemolytic pneumolysin and was involved in cytokine production and maintenance of the pulmonary microvascular barrier. Overall, the inflammasome pathway is protective in pneumonia caused by pneumococci expressing hemolytic toxin but is not activated by clinically important pneumococcal sequence types causing invasive disease. The study indicates that a virulence factor polymorphism may substantially affect the recognition of bacteria by the innate immune system.

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Section: Production Of Il-1b In S Pneumoniae-infected Cellsmentioning

confidence: 73%

The NLRP3 Inflammasome Is Differentially Activated by Pneumolysin Variants and Contributes to Host Defense in Pneumococcal Pneumonia

Witzenrath

Pache

Lorenz

et al. 2011

The Journal of Immunology

225

201

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“…This release also required NLRP3 and pneumolysin (28). Similarly, Shoma et al (41) reported a critical involvement of pneumolysin in IL-1b generation by murine peritoneal macrophages after exposure to S. pneumoniae. Besides activating caspase-1, pneumolysin was shown to induce the cellular production of IL-1 family cytokines in a TLR4-dependent manner.…”

Section: Discussionmentioning

confidence: 98%

The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release

Hoegen

Tremel

Klein

et al. 2011

The Journal of Immunology

195

166

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Streptococcus pneumoniae meningitis causes brain damage through inflammation-related pathways whose identity and mechanisms of action are yet unclear. We previously identified caspase-1, which activates precursor IL-1 type cytokines, as a central mediator of inflammation in pneumococcal meningitis. In this study, we demonstrate that lack of the inflammasome components ASC or NLRP3 that are centrally involved in caspase-1 activation decreases scores of clinical and histological disease severity as well as brain inflammation in murine pneumococcal meningitis. Using specific inhibitors (anakinra and rIL-18–binding protein), we further show that ASC- and NLRP3-dependent pathologic alterations are solely related to secretion of both IL-1β and IL-18. Moreover, using differentiated human THP-1 cells, we demonstrate that the pneumococcal pore-forming toxin pneumolysin is a key inducer of IL-1β expression and inflammasome activation upon pneumococcal challenge. The latter depends on the release of ATP, lysosomal destabilization (but not disruption), and cathepsin B activation. The in vivo importance of this pathway is supported by our observation that the lack of pneumolysin and cathepsin B inhibition is associated with a better clinical course and less brain inflammation in murine pneumococcal meningitis. Collectively, our study indicates a central role of the NLRP3 inflammasome in the pathology of pneumococcal meningitis. Thus, interference with inflammasome activation might be a promising target for adjunctive therapy of this disease.

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“…Several reports have shown that the Δply strain, an S. pneumoniae mutant deficient for the ply gene, is incapable of inducing the production of IL-1␣, IL-1␤, and IL-18 (8)(9)(10)(11)(12). IL-1 family cytokines, including IL-1␣, IL-1␤, and IL-18, have been reported to contribute to host defense and tissue damage in pneumococcal infection models in mice (13)(14)(15)(16)(17)(18).…”

mentioning

confidence: 99%

“…The functional role of PLY has been studied, and it is recognized as a double-edged sword during host-pathogen interactions. Besides its cytotoxic function as a virulence factor, several reports demonstrated that PLY is involved in the activation of host innate immune responses, generating inflammation or contributing to the host defense against S. pneumoniae (4,(6)(7)(8).…”

mentioning

confidence: 99%

“…Upon infection with S. pneumoniae, macrophages secrete a series of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-␣), interleukin-6 (IL-6), IL-12, IL-18, IL-1␣, and IL-1␤ (8). Several reports have shown that the Δply strain, an S. pneumoniae mutant deficient for the ply gene, is incapable of inducing the production of IL-1␣, IL-1␤, and IL-18 (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

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Pneumolysin-Dependent Calpain Activation and Interleukin-1α Secretion in Macrophages Infected with Streptococcus pneumoniae

Fang

et al. 2017

Infect Immun

Self Cite

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Pneumolysin (PLY), a major virulence factor of Streptococcus pneumoniae, is a pore-forming cytolysin that modulates host innate responses contributing to host defense against and pathogenesis of pneumococcal infections. Interleukin-1␣ (IL-1␣) has been shown to be involved in tissue damage in a pneumococcal pneumonia model; however, the mechanism by which this cytokine is produced during S. pneumoniae infection remains unclear. In this study, we examined the role of PLY in IL-1␣ production. Although the strains induced similar levels of pro-IL-1␣ expression, wild-type S. pneumoniae D39, but not a deletion mutant of the ply gene (Δply), induced the secretion of mature IL-1␣ from host macrophages, suggesting that PLY is critical for the maturation and secretion of IL-1␣ during S. pneumoniae infection. Further experiments with calcium chelators and calpain inhibitors indicated that extracellular calcium ions and calpains (calcium-dependent proteases) facilitated the maturation and secretion of IL-1␣ from D39-infected macrophages. Moreover, we found that PLY plays a critical role in calcium influx and calpain activation, as elevated intracellular calcium levels and the degradation of the calpain substrate ␣-fodrin were detected in macrophages infected with D39 but not the Δply strain. These results suggested that PLY induces the influx of calcium in S. pneumoniae-infected macrophages, followed by calpain activation and subsequent IL-1␣ maturation and secretion.KEYWORDS Streptococcus pneumoniae, IL-1␣, pneumolysin, calpain S treptococcus pneumoniae is a classic Gram-positive extracellular pathogen that is responsible for significant mortality and morbidity worldwide, causing bacterial pneumonia, otitis media, meningitis, and septicemia. Due to the severe disease burden and mortality in newborns, elderly persons, and immunocompromised patients and the increasing incidence of drug-resistant clinical isolates, it is critically important to understand the pathogenesis of pneumococcal diseases in order to develop novel therapy methods and effective vaccines (1, 2). Pneumolysin (PLY), a 53-kDa protein toxin encoded by the ply gene, is a key virulence factor of S. pneumoniae and is produced by virtually all clinical isolates. It has been regarded as a candidate for vaccine development against pneumococcal infection (3, 4). PLY is one of the cholesterol-dependent cytolysins, forming ring-or arc-shaped transmembrane pores on cholesterol-containing membranes, eventually causing cytolysis in various cells (5). The functional role of PLY has been studied, and it is recognized as a double-edged sword during host-pathogen interactions. Besides its cytotoxic function as a virulence factor, several reports demonstrated that PLY is involved in the activation of host innate immune responses,

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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

Cited by 70 publications

References 58 publications

The NLRP3 Inflammasome Is Differentially Activated by Pneumolysin Variants and Contributes to Host Defense in Pneumococcal Pneumonia

The NLRP3 Inflammasome Is Differentially Activated by Pneumolysin Variants and Contributes to Host Defense in Pneumococcal Pneumonia

The NLRP3 Inflammasome Contributes to Brain Injury in Pneumococcal Meningitis and Is Activated through ATP-Dependent Lysosomal Cathepsin B Release

Pneumolysin-Dependent Calpain Activation and Interleukin-1α Secretion in Macrophages Infected with Streptococcus pneumoniae

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