{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:17:58Z","timestamp":1791296278710,"version":"4.1.0"},"reference-count":88,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2016,8,1]],"date-time":"2016-08-01T00:00:00Z","timestamp":1470009600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"French Region ile de France","award":["DIM-Malinf"],"award-info":[{"award-number":["DIM-Malinf"]}]},{"DOI":"10.13039\/501100003762","name":"Institut Pasteur","doi-asserted-by":"publisher","award":["PTR 256"],"award-info":[{"award-number":["PTR 256"]}],"id":[{"id":"10.13039\/501100003762","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Infect Immun"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The pathogenicity of<jats:named-content content-type=\"genus-species\">Clostridium difficile<\/jats:named-content>is linked to its ability to produce two toxins: TcdA and TcdB. The level of toxin synthesis is influenced by environmental signals, such as phosphotransferase system (PTS) sugars, biotin, and amino acids, especially cysteine. To understand the molecular mechanisms of cysteine-dependent repression of toxin production, we reconstructed the sulfur metabolism pathways of<jats:named-content content-type=\"genus-species\">C. difficile<\/jats:named-content>strain 630<jats:italic>in silico<\/jats:italic>and validated some of them by testing<jats:named-content content-type=\"genus-species\">C. difficile<\/jats:named-content>growth in the presence of various sulfur sources. High levels of sulfide and pyruvate were produced in the presence of 10 mM cysteine, indicating that cysteine is actively catabolized by cysteine desulfhydrases. Using a transcriptomic approach, we analyzed cysteine-dependent control of gene expression and showed that cysteine modulates the expression of genes involved in cysteine metabolism, amino acid biosynthesis, fermentation, energy metabolism, iron acquisition, and the stress response. Additionally, a sigma factor (SigL) and global regulators (CcpA, CodY, and Fur) were tested to elucidate their roles in the cysteine-dependent regulation of toxin production. Among these regulators, only<jats:italic>sigL<\/jats:italic>inactivation resulted in the derepression of toxin gene expression in the presence of cysteine. Interestingly, the<jats:italic>sigL<\/jats:italic>mutant produced less pyruvate and H<jats:sub>2<\/jats:sub>S than the wild-type strain. Unlike cysteine, the addition of 10 mM pyruvate to the medium for a short time during the growth of the wild-type and<jats:italic>sigL<\/jats:italic>mutant strains reduced expression of the toxin genes, indicating that cysteine-dependent repression of toxin production is mainly due to the accumulation of cysteine by-products during growth. Finally, we showed that the effect of pyruvate on toxin gene expression is mediated at least in part by the two-component system CD2602-CD2601.<\/jats:p>","DOI":"10.1128\/iai.00121-16","type":"journal-article","created":{"date-parts":[[2016,6,14]],"date-time":"2016-06-14T02:29:34Z","timestamp":1465871374000},"page":"2389-2405","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":94,"title":["Control of Clostridium difficile Physiopathology in Response to Cysteine Availability"],"prefix":"10.1128","volume":"84","author":[{"given":"Thomas","family":"Dubois","sequence":"first","affiliation":[{"name":"Laboratoire Pathogen\u00e8se des Bact\u00e9ries Ana\u00e9robies, Institut Pasteur, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Dancer-Thibonnier","sequence":"additional","affiliation":[{"name":"Laboratoire Pathogen\u00e8se des Bact\u00e9ries Ana\u00e9robies, Institut Pasteur, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Monot","sequence":"additional","affiliation":[{"name":"Laboratoire Pathogen\u00e8se des Bact\u00e9ries Ana\u00e9robies, Institut Pasteur, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Hamiot","sequence":"additional","affiliation":[{"name":"Laboratoire Pathogen\u00e8se des Bact\u00e9ries Ana\u00e9robies, Institut Pasteur, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Bouillaut","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Soutourina","sequence":"additional","affiliation":[{"name":"Laboratoire Pathogen\u00e8se des Bact\u00e9ries Ana\u00e9robies, Institut Pasteur, Paris, France"},{"name":"Universit\u00e9 Paris 7-Denis Diderot, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Martin-Verstraete","sequence":"additional","affiliation":[{"name":"Laboratoire Pathogen\u00e8se des Bact\u00e9ries Ana\u00e9robies, Institut Pasteur, Paris, France"},{"name":"Universit\u00e9 Paris 7-Denis Diderot, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Dupuy","sequence":"additional","affiliation":[{"name":"Laboratoire Pathogen\u00e8se des Bact\u00e9ries Ana\u00e9robies, Institut Pasteur, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00082-09"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002317"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.101126598"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05739.x"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002727"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.44.2.353-358.2006"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1998.00663.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.4.1784-1793.2003"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.47676-0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01492-12"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.2008\/019778-0"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.10.5881-5888.2000"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2010.07495.x"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05906.x"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00272-11"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00882-09"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00341-10"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks864"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4114"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-10-234"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.11.6823-6830.2001"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2002.tb05953.x"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002036"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01058-10"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.185.22.6592-6599.2003"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2009.06910.x"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000894"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2006.8.753"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00114-006-0106-1"},{"key":"e_1_3_3_31_2","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1007\/7171_2006_060","volume-title":"Amino acid biosynthesis-pathways, regulation and metabolic engineering","author":"Gu\u00e9don E","year":"2007","unstructured":"Gu\u00e9don E, Martin-Verstraete I. 2007. Cysteine metabolism and its regulation in bacteria, p 195\u2013218. In Wendisch VF (ed), Amino acid biosynthesis-pathways, regulation and metabolic engineering. Springer, Berlin, Germany."},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01273-06"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2004.09.007"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00026-08"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.188.6.2184-2197.2006"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2009.06760.x"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.263889"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mimet.2006.12.001"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M805951200"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mimet.2007.05.021"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mimet.2009.05.004"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2004.07.055"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1046-2023(03)00155-5"},{"key":"e_1_3_3_45_2","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini Y","year":"1995","unstructured":"Benjamini Y, Hochberg Y. 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc Ser 57:289\u2013300.","journal-title":"J R Statist Soc Ser"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1830"},{"key":"e_1_3_3_47_2","first-page":"129","article-title":"The molecular evolution of pyridoxal-5\u2032-phosphate-dependent enzymes","volume":"74","author":"Mehta PK","year":"2000","unstructured":"Mehta PK, Christen P. 2000. The molecular evolution of pyridoxal-5\u2032-phosphate-dependent enzymes. Adv Enzymol Relat Areas Mol Biol 74:129\u2013184.","journal-title":"Adv Enzymol Relat Areas Mol Biol"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn601"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.187.11.3889-3893.2005"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.64.9.3327-3331.1998"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00019-06"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02383-14"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01923-14"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-015-0614-2"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.resmic.2003.11.008"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh659"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1003493"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.186.15.4875-4884.2004"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.71.7.4149-4152.2005"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj20030429"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.145.2.1031-1035.1981"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10534-006-9070-7"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.056978-0"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.188.10.3664-3673.2006"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00098-15"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01423-09"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.2175\/106143007X221328"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01370-06"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00738-10"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1261\/rna.819308"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00937-10"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-11-555"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2013.00059"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1007\/s002840010164"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.06046-11"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fm.2012.05.005"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6968.2006.00405.x"},{"key":"e_1_3_3_78_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01167-07"},{"key":"e_1_3_3_79_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-12-385"},{"key":"e_1_3_3_80_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.02051-12"},{"key":"e_1_3_3_81_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2859-11-122"},{"key":"e_1_3_3_82_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00572-12"},{"key":"e_1_3_3_83_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.26860-0"},{"key":"e_1_3_3_84_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.02768-14"},{"key":"e_1_3_3_85_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2010.12.012"},{"key":"e_1_3_3_86_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.72.1.946-949.2006"},{"key":"e_1_3_3_87_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00205-08"},{"key":"e_1_3_3_88_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.45790-0"},{"key":"e_1_3_3_89_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05315.x"}],"container-title":["Infection and Immunity"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/IAI.00121-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/IAI.00121-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T16:12:22Z","timestamp":1718640742000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/IAI.00121-16"}},"subtitle":[],"editor":[{"given":"V. B.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2016,8]]},"references-count":88,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2016,8]]}},"alternative-id":["10.1128\/IAI.00121-16"],"URL":"https:\/\/doi.org\/10.1128\/iai.00121-16","relation":{},"ISSN":["0019-9567","1098-5522"],"issn-type":[{"value":"0019-9567","type":"print"},{"value":"1098-5522","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8]]},"assertion":[{"value":"2016-02-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-05-31","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-07-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}