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

Abstract

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.

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…Accumulating evidence indicates that NLRP3 inflammasomes play a significant role in the recognition of and response to bacterial infection. Although there is no direct evidence for the interaction of bacterial ligands with NLRP3, a variety of pathogenic bacteria including Staphylococcus aureus (Craven et al 2009;Holzinger et al 2012;Kebaier et al 2012;Maher et al 2013;McGilligan et al 2013;Muñoz-Planillo et al 2009), Streptococcus pneumoniae (Hoegen et al 2011;McNeela et al 2010;Witzenrath et al 2011) and Listeria monocytogenes (Meixenberger et al 2010) have been Arch. Immunol.…”

Alveolar macrophages in pulmonary host defence – the unrecognized role of apoptosis as a mechanism of intracellular bacterial killing

“…Although the toxin itself causes membrane pores we have no evidence that it causes pores in the lysosomal membrane, as exposure to bacteria expressing toxin lacking pore-forming capability still induce comparable levels of apoptosis to bacteria expressing wild-type toxin (Bewley et al, manuscript submitted). Equally, we have not found any role to date for components of the intracellular recognition systems for pneumolysin, which involve nucleotidebinding oligomerization domain containing protein (Nod)-like receptor (NLR) P3 or the absent in melanoma (AIM) 2 NLR, in the response to pneumolysin that leads to lysosomal membrane permeabilization or to induction of apoptosis [86][87][88]. The induction of lysosomal membrane permeabilization, cathepsin D activation and induction of apoptosis is not a response limited to S. pneumoniae, as it occurs with a range of other extracellular bacteria [80].…”

Streptococcus pneumoniaeStimulates a STING- and IFN Regulatory Factor 3-Dependent Type I IFN Production in Macrophages, which Regulates RANTES Production in Macrophages, Cocultured Alveolar Epithelial Cells, and Mouse Lungs

“…In contrast, other NLRs and the PYHIN protein absent in melanoma 2 (AIM2) regulate IL-1 family cytokines on a posttranslational level (3,4). The TLRs TLR2, TLR4, and TLR9 and the NLRs NOD2 and NLRP3 have been shown to control the production of several proinflammatory cytokines during S. pneumoniae infection (2,(5)(6)(7)(8)(9)(10)(11)(12).…”