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We hypothesized that this temperature change may regulate genes essential for infection.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Microarray analysis of <jats:italic>F. tularensis<\/jats:italic> LVS shifted from 26\u00b0C (environmental) to 37\u00b0C (mammalian) showed ~11% of this bacterium's genes were differentially-regulated. Importantly, 40% of the protein-coding genes that were induced at 37\u00b0C have been previously implicated in virulence or intracellular growth of <jats:italic>Francisella<\/jats:italic> in other studies, associating the bacterial response to this temperature shift with pathogenesis. Forty-four percent of the genes induced at 37\u00b0C encode proteins of unknown function, suggesting novel <jats:italic>Francisella<\/jats:italic> virulence traits are regulated by mammalian temperature. To explore this possibility, we generated two mutants of loci induced at 37\u00b0C [FTL_1581 and FTL_1664 (<jats:italic>deoB<\/jats:italic>)]. The FTL_1581 mutant was attenuated in a chicken embryo infection model, which was likely attributable to a defect in survival within macrophages. FTL_1581 encodes a novel hypothetical protein that we suggest naming <jats:italic>t<\/jats:italic>emperature-<jats:italic>i<\/jats:italic>nduced, <jats:italic>v<\/jats:italic>irulence-associated locus <jats:italic>A<\/jats:italic>, <jats:italic>tivA<\/jats:italic>. Interestingly, the <jats:italic>deoB<\/jats:italic> mutant showed diminished entry into mammalian cells compared to wild-type LVS, including primary human macrophages and dendritic cells, the macrophage-like RAW 264.7 line, and non-phagocytic HEK-293 cells. This is the first study identifying a <jats:italic>Francisella<\/jats:italic> gene that contributes to uptake into both phagocytic and non-phagocytic host cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>Our results provide new insight into mechanisms of <jats:italic>Francisella<\/jats:italic> virulence regulation and pathogenesis. <jats:italic>F. tularensis<\/jats:italic> LVS undergoes considerable gene expression changes in response to mammalian body temperature. This temperature shift is important for the regulation of genes that are critical for the pathogenesis of <jats:italic>Francisella<\/jats:italic>. Importantly, the compilation of temperature-regulated genes also defines a rich collection of novel candidate virulence determinants, including <jats:italic>tivA<\/jats:italic> (FTL_1581). An analysis of <jats:italic>tivA<\/jats:italic> and <jats:italic>deoB<\/jats:italic> (FTL_1664) revealed that these genes contribute to intracellular survival and entry into mammalian cells, respectively.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2180-8-172","type":"journal-article","created":{"date-parts":[[2008,10,8]],"date-time":"2008-10-08T18:23:37Z","timestamp":1223490217000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["Global transcriptional response to mammalian temperature provides new insight into Francisella tularensis pathogenesis"],"prefix":"10.1186","volume":"8","author":[{"given":"Joseph","family":"Horzempa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Paul E","family":"Carlson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn M","family":"O'Dee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert MQ","family":"Shanks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard J","family":"Nau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2008,10,8]]},"reference":[{"issue":"4","key":"605_CR1","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1128\/CMR.15.4.631-646.2002","volume":"15","author":"J Ellis","year":"2002","unstructured":"Ellis J, Oyston PC, Green M, Titball RW: Tularemia. 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