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Title: Iron regulated genes of Salmonella enterica serovar Typhimurium in response to norepinephrine and the requirement of fepCDG for norepinephrine-enhanced growth

item Bearson, Bradley - Brad
item Bearson, Shawn
item Dowd, Scot
item Toscano, Michael
item Lay Jr, Donald

Submitted to: Microbes and Infection
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/17/2008
Publication Date: 7/2/2008
Citation: Bearson, B.L., Bearson, S.M., Uthe, J., Houghton, J., Dowd, S.E., Lee, I., Toscano, M.J., Lay Jr, D.C. 2008. Iron regulated genes of Salmonella enterica serovar Typhimurium in response to norepinephrine and the requirement of fepCDG for norepinephrine-enhanced growth. Microbes and Infection. 10(7):807-816.

Interpretive Summary: Mammalian serum contains the protein transferrin which sequesters iron, thereby preventing bacterial growth in the circulatory system. The body, however, produces the stress hormone norepinephrine which has been shown to enhance the growth of Salmonella Typhimurium in mouse serum, possibly by providing bacteria with an available source of iron. This study identified specific genes required for norepinephrine-enhanced growth of Salmonella Typhimurium and mutations in these iron-acquisition genes allowing for Salmonella Typhimurium to colonize the gastrointestinal tract in pigs. Data indicated that mutations in the norepinephrine-response genes did not decrease Salmonella Typhimurium colonization in the pig gastrointestinal tract, thereby contradicting results obtained in mice. This data is important to the scientific community investigating intervention strategies for reduction of Salmonella proliferation in the body.

Technical Abstract: The presence of catecholamines in vivo may stimulate enteric bacteria including the foodborne pathogen Salmonella enterica serovar Typhimurium by two mechanisms, acting as a quorum sensing signal and providing iron in the presence of serum. To identify genes of Salmonella Typhimurium that participate in the response of the pathogen to norepinephrine exposure, both transposon mutagenesis and DNA microarray analysis were performed. Insertional mutations in the following Salmonella Typhimurium genes decreased norepinephrine-enhanced growth: degS, entE, entF, fes, gpmA, hfq, STM 3846, wzxE and ycgQ. DNA microarray and real-time RT-PCR analyses revealed a decrease in the expression of several genes involved in iron acquisition and utilization during norepinephrine exposure, signifying the iron-deplete conditions of SAPI serum minimal medium and the siderophore-like activity of norepinephrine to supply Salmonella with iron. Unlike the wild-type parent strain, growth of a Salmonella Typhimurium mutant containing deletional mutations in the cirA iroN fepA genes encoding iron-regulated outer membrane proteins was not enhanced by norepinephrine. Similar results were observed for a mutation in the fepC gene, an inner membrane protein involved in enterochelin transport into the cellular cytoplasm. However, growth of both the fepC and the cirA iroN fepA mutants could be rescued in the presence of an alternative siderphore, ferrioxamine E, further validating the role of norepinephrine in supplying the organism with iron via the catecholate-specific iron transport system. Contrary to previous reports using the mouse model, the cirA iroN fepA mutant of Salmonella Typhimurium colonized the swine gastrointestinal tract, as did the fepC mutant.