{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T04:59:08Z","timestamp":1761541148224},"reference-count":48,"publisher":"Microbiology Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,7,1]]},"abstract":"<jats:p>\n                  <jats:italic>Rickettsia conorii<\/jats:italic>, the causative agent of Mediterranean spotted fever, preferentially infects human microvascular endothelium and activates pro-inflammatory innate immune responses as evidenced by enhanced expression and secretion of cytokines and chemokines. Our recent studies reveal that human microvascular endothelial cells (HMECs) infected with <jats:italic>R. conorii<\/jats:italic> also launch \u2018antiviral\u2019 host defence mechanisms typically governed by type I interferons. To summarize, infected HMECs secrete IFN-\u03b2 to activate STAT1 in an autocrine\/paracrine manner and display increased expression of IFN-stimulated genes, for example <jats:italic>ISG15<\/jats:italic>, which in turn activate innate responses to interfere with intracellular replication of rickettsiae. We now present evidence that UBP43 and SOCS1, known negative regulators of JAK\/STAT signalling, are also induced in <jats:italic>R. conorii-<\/jats:italic>infected HMECs, of which UBP43 but not SOCS1 functions to negatively regulate STAT1 activation. Interestingly, UBP43 induction is almost completely abolished in the presence of IFN-\u03b2-neutralizing antibody, implicating an important role for UBP43 as a feedback inhibitor for IFN-\u03b2-mediated STAT1 activation. In contrast, SOCS1 expression is only partially affected by IFN-\u03b2 neutralization, implicating potential involvement of as-yet-unidentified IFN-independent mechanism(s) in <jats:italic>SOCS1<\/jats:italic> induction during <jats:italic>R. conorii<\/jats:italic> infection. A number of IFN-stimulated genes, including <jats:italic>ISG15<\/jats:italic>, <jats:italic>OAS1<\/jats:italic>, <jats:italic>MX1<\/jats:italic>, <jats:italic>IRF1<\/jats:italic>, <jats:italic>IRF9<\/jats:italic> and <jats:italic>TAP1<\/jats:italic> are also induced in an IFN-\u03b2-dependent manner, whereas <jats:italic>GBP1<\/jats:italic> remains unaffected by IFN-\u03b2 neutralization. Increased STAT1 phosphorylation in HMECs subjected to <jats:italic>UBP43<\/jats:italic> knockdown led to transcriptional activation of <jats:italic>OAS1<\/jats:italic>, <jats:italic>MX1<\/jats:italic> and <jats:italic>GBP1<\/jats:italic>, confirming the negative regulatory role of UBP43. Although <jats:italic>IRF1<\/jats:italic>, <jats:italic>IRF9<\/jats:italic> and <jats:italic>TAP1<\/jats:italic> were induced by IFN-\u03b2, siRNA-mediated silencing of <jats:italic>UBP43<\/jats:italic> or <jats:italic>SOCS1<\/jats:italic> did not significantly affect their transcriptional activation. Expression of <jats:italic>ISG15<\/jats:italic> was, however, increased in HMECs transfected with siRNA for <jats:italic>UBP43<\/jats:italic> and <jats:italic>SOCS1<\/jats:italic>. Thus, unique regulatory patterns of induced expression of <jats:italic>UBP43<\/jats:italic>, <jats:italic>SOCS1<\/jats:italic> and IFN-stimulated genes represent pathogen-specific responses underlying IFN-\u03b2-mediated host endothelial signalling during the pathogenesis of spotted fever group rickettsiosis.<\/jats:p>","DOI":"10.1099\/jmm.0.054502-0","type":"journal-article","created":{"date-parts":[[2013,4,5]],"date-time":"2013-04-05T04:29:13Z","timestamp":1365136153000},"page":"968-979","source":"Crossref","is-referenced-by-count":22,"title":["Suppressor of cytokine signalling protein SOCS1 and UBP43 regulate the expression of type I interferon-stimulated genes in human microvascular endothelial cells infected with Rickettsia conorii"],"prefix":"10.1099","volume":"62","author":[{"given":"Punsiri M.","family":"Colonne","sequence":"first","affiliation":[{"name":"Microbiology and Immunology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abha","family":"Sahni","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjeev K.","family":"Sahni","sequence":"additional","affiliation":[{"name":"Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA"},{"name":"Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"345","reference":[{"key":"r1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80047-1"},{"key":"r2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)00028-5"},{"key":"r3","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5344.1803"},{"key":"r4","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(90)90292-Y"},{"key":"r5","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.05008-11"},{"key":"r6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2011.11.015"},{"key":"r7","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700294"},{"key":"r8","doi-asserted-by":"publisher","DOI":"10.1126\/science.7517574"},{"key":"r9","doi-asserted-by":"crossref","first-page":"5147","DOI":"10.1128\/MCB.11.10.5147","article-title":"Two distinct alpha-interferon-dependent signal transduction pathways may contribute to activation of transcription of the guanylate-binding protein gene","volume":"11","author":"Decker","year":"1991","journal-title":"Mol Cell Biol"},{"key":"r10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.16.7840"},{"key":"r11","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1155\/2010\/470468","article-title":"SOCS1, a negative regulator of cytokine signals and TLR responses, in human liver diseases","volume":"2010","author":"Fujimoto","year":"2010","journal-title":"Gastroenterol Res Pract"},{"key":"r12","doi-asserted-by":"crossref","first-page":"2109","DOI":"10.1182\/blood.V82.7.2109.2109","article-title":"Demonstration of Rickettsia conorii-induced endothelial injury in vivo by measuring circulating endothelial cells, thrombomodulin, and von Willebrand factor in patients with Mediterranean spotted fever","volume":"82","author":"George","year":"1993","journal-title":"Blood"},{"key":"r13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0701849104"},{"key":"r14","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.20.5568"},{"key":"r15","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg382"},{"key":"r16","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(89)90107-4"},{"key":"r17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010074200"},{"key":"r18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118354"},{"key":"r19","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0004(02)02085-6"},{"key":"r20","doi-asserted-by":"publisher","DOI":"10.1126\/science.1201711"},{"key":"r21","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90351-8"},{"key":"r22","doi-asserted-by":"publisher","DOI":"10.1101\/gad.3.9.1362"},{"key":"r23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.10.5267"},{"key":"r24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902728"},{"key":"r25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109078200"},{"key":"r26","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601149"},{"key":"r27","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/967852"},{"key":"r28","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.83.8.815"},{"key":"r29","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(88)91307-4"},{"key":"r30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2010.01478.x"},{"key":"r31","doi-asserted-by":"publisher","DOI":"10.1038\/43219"},{"key":"r32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000196"},{"key":"r33","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-5493fje"},{"key":"r34","doi-asserted-by":"crossref","first-page":"845","DOI":"10.4269\/ajtmh.1986.35.845","article-title":"Mediterranean spotted fever: clinical, laboratory and epidemiological features of 199 cases","volume":"35","author":"Raoult","year":"1986","journal-title":"Am J Trop Med Hyg"},{"key":"r35","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.47050-0"},{"key":"r36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2008.02248.x"},{"key":"r37","doi-asserted-by":"crossref","first-page":"5833","DOI":"10.4049\/jimmunol.164.11.5833","article-title":"IFN regulatory factor-1-mediated transcriptional activation of mouse STAT-induced STAT inhibitor-1 gene promoter by IFN-gamma","volume":"164","author":"Saito","year":"2000","journal-title":"J Immunol"},{"key":"r38","first-page":"429","article-title":"[Epidemiologic features of Mediterranean spotted fever in Portugal]","volume":"16","author":"Sousa","year":"2003","journal-title":"Acta Med Port"},{"key":"r39","doi-asserted-by":"crossref","first-page":"2786","DOI":"10.1128\/IAI.65.7.2786-2791.1997","article-title":"Rickettsia rickettsii infection of cultured human endothelial cells induces NF-\u03baB activation","volume":"65","author":"Sporn","year":"1997","journal-title":"Infect Immun"},{"key":"r40","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(86)90493-9"},{"key":"r41","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006499"},{"key":"r42","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63494-3"},{"key":"r43","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(05)80068-6"},{"key":"r44","first-page":"129","article-title":"Cytokine-induced, nitric oxide-dependent, intracellular antirickettsial activity of mouse endothelial cells","volume":"76","author":"Walker","year":"1997","journal-title":"Lab Invest"},{"key":"r45","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.3.1841-1846.2001"},{"key":"r46","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.24.15417-15429.2005"},{"key":"r47","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.12.6282-6286.2004"},{"key":"r48","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1128\/MCB.19.3.2416","article-title":"Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak\/STAT pathway","volume":"19","author":"You","year":"1999","journal-title":"Mol Cell Biol"}],"container-title":["Journal of Medical Microbiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/jmm\/10.1099\/jmm.0.054502-0?crawler=true","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,10,2]],"date-time":"2020-10-02T03:16:39Z","timestamp":1601608599000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/jmm\/10.1099\/jmm.0.054502-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,7,1]]},"references-count":48,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2013,7,1]]}},"URL":"https:\/\/doi.org\/10.1099\/jmm.0.054502-0","relation":{},"ISSN":["0022-2615","1473-5644"],"issn-type":[{"value":"0022-2615","type":"print"},{"value":"1473-5644","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,7,1]]}}}