{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:13:07Z","timestamp":1790935987162,"version":"4.1.0"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2011,1,25]],"date-time":"2011-01-25T00:00:00Z","timestamp":1295913600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2011,3,1]],"date-time":"2011-03-01T00:00:00Z","timestamp":1298937600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2011,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:named-content content-type=\"genus-species\">Clostridium perfringens<\/jats:named-content>\n            vegetative cells cause both histotoxic infections (e.g., gas gangrene) and diseases originating in the intestines (e.g., hemorrhagic necrotizing enteritis or lethal enterotoxemia). Despite their medical and veterinary importance, the molecular pathogenicity of\n            <jats:named-content content-type=\"genus-species\">C. perfringens<\/jats:named-content>\n            vegetative cells causing diseases of intestinal origin remains poorly understood. However,\n            <jats:named-content content-type=\"genus-species\">C. perfringens<\/jats:named-content>\n            beta toxin (CPB) was recently shown to be important when vegetative cells of\n            <jats:named-content content-type=\"genus-species\">C. perfringens<\/jats:named-content>\n            type C strain CN3685 induce hemorrhagic necrotizing enteritis and lethal enterotoxemia. Additionally, the VirS\/VirR two-component regulatory system was found to control CPB production by CN3685 vegetative cells during aerobic infection of cultured enterocyte-like Caco-2 cells. Using an isogenic\n            <jats:italic>virR<\/jats:italic>\n            null mutant, the current study now reports that the VirS\/VirR system also regulates CN3685 cytotoxicity during infection of Caco-2 cells under anaerobic conditions, as found in the intestines. More importantly, the\n            <jats:italic>virR<\/jats:italic>\n            mutant lost the ability to cause hemorrhagic necrotic enteritis in rabbit small intestinal loops. Western blot analyses demonstrated that the VirS\/VirR system mediates necrotizing enteritis, at least in part, by controlling\n            <jats:italic>in vivo<\/jats:italic>\n            CPB production. In addition, vegetative cells of the isogenic\n            <jats:italic>virR<\/jats:italic>\n            null mutant were, relative to wild-type vegetative cells, strongly attenuated in their lethality in a mouse enterotoxemia model. Collectively, these results identify the first regulator of\n            <jats:italic>in vivo<\/jats:italic>\n            pathogenicity for\n            <jats:named-content content-type=\"genus-species\">C. perfringens<\/jats:named-content>\n            vegetative cells causing disease originating in the complex intestinal environment. Since VirS\/VirR also mediates histotoxic infections, this two-component regulatory system now assumes a global role in regulating a spectrum of infections caused by\n            <jats:named-content content-type=\"genus-species\">C. perfringens<\/jats:named-content>\n            vegetative cells.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            <jats:named-content content-type=\"genus-species\">Clostridium perfringens<\/jats:named-content>\n            is an important human and veterinary pathogen.\n            <jats:named-content content-type=\"genus-species\">C. perfringens<\/jats:named-content>\n            vegetative cells cause both histotoxic infections, e.g., traumatic gas gangrene, and infections originating when this bacterium grows in the intestines. The VirS\/VirR two-component regulatory system has been shown to control the pathogenicity of\n            <jats:named-content content-type=\"genus-species\">C. perfringens<\/jats:named-content>\n            type A strains in a mouse gas gangrene model, but there is no understanding of pathogenicity regulation when\n            <jats:named-content content-type=\"genus-species\">C. perfringens<\/jats:named-content>\n            vegetative cells cause disease originating in the complex intestinal environment. The current study establishes that VirS\/VirR controls vegetative cell pathogenicity when\n            <jats:named-content content-type=\"genus-species\">C. perfringens<\/jats:named-content>\n            type C isolates cause hemorrhagic necrotic enteritis and lethal enterotoxemia (i.e., toxin absorption from the intestines into the circulation, allowing targeting of internal organs). This effect involves VirS\/VirR-mediated regulation of beta toxin production\n            <jats:italic>in vivo<\/jats:italic>\n            . Therefore, VirS\/VirR is the first identified global\n            <jats:italic>in vivo<\/jats:italic>\n            regulator controlling the ability of\n            <jats:named-content content-type=\"genus-species\">C. perfringens<\/jats:named-content>\n            vegetative cells to cause gas gangrene and, at least some, intestinal infections.\n          <\/jats:p>","DOI":"10.1128\/mbio.00338-10","type":"journal-article","created":{"date-parts":[[2011,1,26]],"date-time":"2011-01-26T04:37:25Z","timestamp":1296016645000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":36,"title":["The VirS\/VirR Two-Component System Regulates the Anaerobic Cytotoxicity, Intestinal Pathogenicity, and Enterotoxemic Lethality of Clostridium perfringens Type C Isolate CN3685"],"prefix":"10.1128","volume":"2","author":[{"given":"Menglin","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Vidal","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliann","family":"Saputo","sequence":"additional","affiliation":[{"name":"California Animal Health and Food Safety Laboratory System, San Bernardino Branch, University of California\u2014Davis, San Bernardino, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce A.","family":"McClane","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Uzal","sequence":"additional","affiliation":[{"name":"California Animal Health and Food Safety Laboratory System, San Bernardino Branch, University of California\u2014Davis, San Bernardino, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","first-page":"688","volume-title":"The prokaryotes","author":"McClane B. A.","year":"2006","unstructured":"McClaneB. A. UzalF. A. MiyakawaM. F. LyerlyD. WilkinsT. . 2006. The enterotoxic clostridia, p. 688\u2013752. In FalkowS. DworkinM. RosenburgE. SchleiferH. StackebrandtE. , The prokaryotes. Springer, New York, NY."},{"key":"e_1_3_2_3_2","first-page":"703","volume-title":"Gram-positive pathogens","author":"McClane B. A.","year":"2006","unstructured":"McClaneB. A. LyerlyD. M. WilkinsT. D. . 2006. Enterotoxic clostridia: Clostridium perfringens type A and Clostridium difficile, p. 703\u2013714. In FischettiV. A. FerrettiJ. J. PortnoyD. A. RoodJ. , Gram-positive pathogens. ASM Press, Washington, DC."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(98)01430-9"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.06007.x"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01672-06"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00534-06"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.11.7413-7421.2005"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-012595020-6\/50010-3"},{"key":"e_1_3_2_10_2","first-page":"198","volume-title":"The clostridia: molecular biology and pathogenesis","author":"Lawrence G. W.","year":"1997","unstructured":"LawrenceG. W. 1997. The pathogenesis of enteritis necroticans, p. 198\u2013207. In RoodJ. I. McClaneB. A. SongerJ. G. TitballR. W. , The clostridia: molecular biology and pathogenesis. Academic Press, London, United Kingdom."},{"key":"e_1_3_2_11_2","first-page":"93","volume-title":"Clostridia in gastrointestinal disease","author":"Walker P. D.","year":"1985","unstructured":"WalkerP. D. 1985. Pig-bel, p. 93\u2013116. In BorrielloS. P. , Clostridia in gastrointestinal disease. CRC Press, Boca Raton, FL."},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200004273421704"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3880491"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1099\/00222615-13-3-445"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00825-09"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.71.11.7542-7547.2005"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00547-08"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.1994.tb01063.x"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.176.6.1616-1623.1994"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.52.1.333"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.anaerobe.2009.10.003"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2009.01332.x"},{"key":"e_1_3_2_23_2","first-page":"715","volume-title":"Gram-positive pathogens","author":"Stevens D. L.","year":"2006","unstructured":"StevensD. L. RoodJ. I. . 2006. Histotoxic clostridia, p. 715\u2013724. In FischettiV. A. NovickR. P. FerrettiJ. J. PortnoyD. A. RoodJ. I. , Gram-positive pathogens, 2nd ed. ASM Press, Washington, DC.","edition":"2"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.12.7904-7910.2001"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000045"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2008.01272.x"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1097(03)00255-6"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00123-10"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0040026"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.022493799"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.5238106"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01455-08"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006232"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00338-10","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.00338-10","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T01:39:51Z","timestamp":1646703591000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.00338-10"}},"subtitle":[],"editor":[{"given":"R. John","family":"Collier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2011,3]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,3]]}},"alternative-id":["10.1128\/mBio.00338-10"],"URL":"https:\/\/doi.org\/10.1128\/mbio.00338-10","relation":{},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,3]]},"assertion":[{"value":"2010-12-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2010-12-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2011-01-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00338-10"}}