title: Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection.
abstract: Streptococcus pneumoniae is a Gram-positive, extracellular bacterium that is responsible for significant mortality and morbidity worldwide. Pneumolysin (PLY), a cytolysin produced by all clinical isolates of the pneumococcus, is one of the most important virulence factors of this pathogen. We have previously reported that PLY is an essential factor for activation of caspase-1 and consequent secretion of IL-1β and IL-18 in macrophages infected with S. pneumoniae. However, the host molecular factors involved in caspase-1 activation are still unclear. To further elucidate the mechanism of caspase-1 activation in macrophages infected with S. pneumoniae, we examined the involvement of inflammasomes in inducing this cellular response. Our study revealed that apoptosis-associated specklike protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors such as nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) and absent in melanoma 2 (AIM2), is essentially required for the induction of caspase-1 activation by S. pneumoniae. Caspase-1 activation was partially impaired in NLRP3(-/-) macrophages, whereas knockdown and knockout of AIM2 resulted in a clear decrease in caspase-1 activation in response to S. pneumoniae. These results suggest that ASC inflammasomes, including AIM2 and NLRP3, are critical for caspase-1 activation induced by S. pneumoniae. Furthermore, ASC(-/-) mice were more susceptible than wild-type mice to S. pneumoniae, with impaired secretion of IL-1β and IL-18 into the bronchoalveolar lavage after intranasal infection, suggesting that ASC inflammasomes contribute to the protection of host from infection with PLY-producing S. pneumoniae.
authors.affiliation: Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
authors.forename: Rendong
authors.initials: R
authors.lastname: Fang
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawamura
authors.forename: Yanna
authors.initials: Y
authors.lastname: Shen
authors.forename: Hideki
authors.initials: H
authors.lastname: Hara
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Sakai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Teresa
authors.initials: T
authors.lastname: Fernandes-Alnemri
authors.forename: Ruili
authors.initials: R
authors.lastname: Yang
authors.forename: Eduardo
authors.initials: E
authors.lastname: Hernandez-Cuellar
authors.forename: Sita R
authors.initials: SR
authors.lastname: Dewamitta
authors.forename: Yanting
authors.initials: Y
authors.lastname: Xu
authors.forename: Huixin
authors.initials: H
authors.lastname: Qu
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
authors.forename: Masao
authors.initials: M
authors.lastname: Mitsuyama
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000502:physiology; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins; D060467:Disease Resistance / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D058847:Inflammasomes / Q000502:physiology*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009687:Nuclear Proteins / Q000502:physiology; D011008:Pneumococcal Infections / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D013301:Streptolysins / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; C498534:Pycard protein, mouse; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D020170:Caspase 1