title: Immunoactive Clostridial Membrane Vesicle Production Is Regulated by a Sporulation Factor.
abstract: Recently, many Gram-positive bacteria as well as Gram-negative bacteria have been reported to produce membrane vesicles (MVs), but little is known regarding the regulators involved in MV formation. We found that a Gram-positive anaerobic pathogen,Clostridium perfringens, produces MVs predominantly containing membrane proteins and cell wall components. These MVs stimulated proinflammatory cytokine production in mouse macrophage-like cells. We suggested that MVs induced interleukin-6 production through the Toll-like receptor 2 (TLR2) signaling pathway. Thus, the MV could have a role in the bacterium-host interaction and bacterial infection pathogenesis. Moreover, we found that the sporulation master regulator genespo0Awas required for vesiculogenesis. A conserved, phosphorylated aspartate residue of Spo0A was indispensable for MV production, suggesting that the phosphorylation of Spo0A triggers MV production. Multiple orphan sensor kinases necessary for sporulation were also required to maximize MV production. These findings imply thatC. perfringensactively produces immunoactive MVs in response to the environment changing, as recognized by membrane-spanning sensor kinases and by modulating the phosphorylation level of Spo0A.
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Obana
authors.affiliation: Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Ryoma
authors.initials: R
authors.lastname: Nakao
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nagayama
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Senpuku
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan nomura.nobuhiko.ge@u.tsukuba.ac.jp.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Nomura
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D003016:Clostridium perfringens / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D054884:Host-Pathogen Interactions; D015850:Interleukin-6; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D022142:Secretory Vesicles / Q000378:metabolism*; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D015850:Interleukin-6; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D014157:Transcription Factors; C577686:interleukin-6, mouse
keywords: Clostridium perfringens; innate immunity; membrane vesicle; sporulation