Critical involvement of pneumolysin in production of interleukin-1 alpha and caspase-1-dependent cytokines in infection with Streptococcus pneumoniae in vitro: a novel function of pneumolysin in caspase-1 activation

• Main Authors: Shereen Shoma, Kohsuke Tsuchiya, Ikuo Kawamura, Takamasa Nomura, Hideki Hara, Ryosuke Uchiyama, Sylvia Daim, Masao Mitsuyama
• Format: Article
• Language: English; English
• Published: American Society for Microbiology 2008
• Subjects: R5-920 Medicine (General)
• Online Access: https://eprints.ums.edu.my/id/eprint/29305/1/Critical%20involvement%20of%20pneumolysin%20in%20production%20of%20interleukin-1%CE%B1%20and%20caspase-1-dependent%20cytokines%20in%20infection%20with%20streptococcus%20pneumoniae%20in%20vitro.pdf; https://eprints.ums.edu.my/id/eprint/29305/2/Critical%20involvement%20of%20pneumolysin%20in%20production%20of%20interleukin-1%CE%B1%20and%20caspase-1-dependent%20cytokines%20in%20infection%20with%20streptococcus%20pneumoniae%20in%20vitro1.pdf; https://eprints.ums.edu.my/id/eprint/29305/; http://iai.asm.org/content/76/4/1547.full; https://doi.org/10.1128/IAI.01269-07

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 (Δply) and a recombinant pneumolysin protein (rPLY) were constructed. Upon infection of macrophages in vitro, the ability to induce the production of interleukin-1α (IL-1α), IL-1β, and IL-18 was severely impaired in the Δply mutant, whereas there was no marked difference in the induction of tumor necrosis factor alpha (TNF-α) and IL-12p40 between the wild type and the Δply mutant of S. pneumoniae. When macrophages were stimulated with rPLY, the production of IL-1α, IL-1β, 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-α, 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 Δply 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.