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A primary factor involved in these host cell interactions is the Dot\/Icm Type IV secretion system responsible for translocating effector proteins needed to establish and maintain the bacterial replicative niche. Several regulatory factors have been identified to control the expression of the Dot\/Icm system and effectors, one of which is the CpxRA two\u2010component system, suggesting essentiality for virulence. In this study, we generated<jats:italic>cpxR<\/jats:italic>,<jats:italic>cpxA<\/jats:italic>and<jats:italic>cpxRA<\/jats:italic>in\u2010frame null mutant strains to further delineate the role of the CpxRA system in bacterial survival and virulence. We found that<jats:italic>cpxR<\/jats:italic>is essential for intracellular replication within<jats:italic>Acanthamoeba castellanii<\/jats:italic>, but not in U937\u2010derived macrophages. Transcriptome analysis revealed that CpxRA regulates a large number of virulence\u2010associated proteins including Dot\/Icm effectors as well as Type II secreted substrates. Furthermore, the<jats:italic>cpxR<\/jats:italic>and<jats:italic>cpxRA<\/jats:italic>mutant strains were more sodium resistant than the parental strain Lp02, and<jats:italic>cpxRA<\/jats:italic>expression reaches maximal levels during postexponential phase. Taken together, our findings suggest the CpxRA system is a key contributor to<jats:italic>L. pneumophila<\/jats:italic>virulence in protozoa via virulence factor regulation.<\/jats:p>","DOI":"10.1111\/mmi.13365","type":"journal-article","created":{"date-parts":[[2016,3,2]],"date-time":"2016-03-02T16:02:54Z","timestamp":1456934574000},"page":"1017-1038","source":"Crossref","is-referenced-by-count":39,"title":["The CpxRA two\u2010component system contributes to<scp><i>L<\/i><\/scp><i>egionella pneumophila<\/i>virulence"],"prefix":"10.1111","volume":"100","author":[{"given":"Jennifer R.","family":"Tanner","sequence":"first","affiliation":[{"name":"Department of Microbiology, Faculty of Science University of Manitoba Winnipeg MB R3T 2N2 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laam","family":"Li","sequence":"additional","affiliation":[{"name":"Faculty of Agricultural and Environmental Sciences, Department of Natural Resource Sciences McGill University 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