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Title: CO-REGULATION OF SALMONELLA ENTERICA GENES REQUIRED FOR VIRULENCE AND RESISTANCE TO ANTIMICROBIAL PEPTIDES BY SLYA AND PHOP/PHOQ

Author
item NAVARRE, WILLIAM - UNIV OF WASHINGTON
item HALSEY, THOMAS - NORTH CAROLINA STATE UNIV
item WALTHERS, DON - UNIV OF ILLINOIS
item Frye, Jonathan
item MCCLELLEND, MICHAEL - SIDNEY KIMMEL CANCER CTR
item POTTER, JENNIFER - NORTH CAROLINA STATE UNIV
item KENNEY, LINDA - UNIV OF ILLINOIS
item GUNN, JOHN - OHIO STATE UNIV
item FANG, FERRIC - UNIV OF WASHINGTON
item LIBBY, STEPHEN - UNIV OF WASHINGTON

Submitted to: Molecular Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/24/2004
Publication Date: 4/1/2005
Citation: Navarre, W.W., Halsey, T.A., Walthers, D., Frye, J.G., Mcclellend, M., Potter, J.L., Kenney, L., Gunn, J.S., Fang, F.C., Libby, S.J. 2005. Co-regulation of salmonella enterica genes required for virulence and resistance to antimicrobial peptides by slya and phop/phoq. Molecular Microbiology. 56(2):492-508.

Interpretive Summary: Salmonella uses complex systems to regulate gene expression in order to establish a successful infection and cause disease. Several proteins including SlyA and PhoP/Q are known to regulate this process; however their coordination is poorly understood. To determine this, the gene expression of a Salmonella strain lacking SlyA was analyzed by DNA microarray. This study revealed that many SlyA-dependent genes are also controlled by the PhoP/Q regulatory system. Many SlyA and PhoP/PhoQ co-regulated genes have been directly implicated in virulence and resistance to antimicrobial peptides. A new model of regulation for these genes was determined by this study and can be used by researchers to understand the complex gene regulation necessary to make Salmonella a successful pathogen. The genes this pathway controls are unique to Salmonella and present possible targets for vaccine or treatment development to control this important pathogen.

Technical Abstract: Analysis of the transcriptome of a slyA mutant Salmonella enterica serovar Typhimurium revealed that many SlyA-dependent genes, including pagC, pagD, ugtL, mig-14, pgtE, pipB2, sopD2, pagJ and pagK, are also controlled by the PhoP/PhoQ regulatory system. Many SlyA and PhoP/PhoQ co-regulated genes have functions associated with the bacterial envelope, and some have been directly implicated in virulence and resistance to antimicrobial peptides. Purified His-tagged SlyA was found to bind to the pagC and mig-14 promoters in regions homologous to a previously proposed “SlyA-box.” The pagC promoter lacked a consensus PhoP-binding site which suggested that the effect of PhoP on pagC transcription was indirect. Stimulation of pagC expression by PhoP was found to require SlyA. However, levels of SlyA protein and mRNA were not significantly changed under low-magnesium PhoP-inducing conditions in which pagC expression was profoundly elevated, which indicated that the PhoP/PhoQ system does not activate pagC expression by altering SlyA protein concentration. Models were proposed in which PhoP may control SlyA activity via a soluble ligand or SlyA may function as an anti-repressor to allow PhoP activation. The absence of most SlyA/PhoP-dependent genes from the Escherichia coli K12 genome suggests that the functional linkage between the SlyA and PhoP/PhoQ regulatory systems arose as Salmonella evolved its distinctive pathogenic lifestyle.