The ability to enter animal cells is a property common to many pathogenic microorganisms. The entry mechanism of these pathogens has been the subject of much research in recent years and several different species and genera have proven to be useful models. The simplest system identified thus far is that of Y. pseudo tuberculosis and Y. enterocolitica, where individual invasion factors (either invasin or Ail) are sufficient to confer the invasive phenotype to non-invasive E. coli. In contrast, entry (invasion) by Salmonella is more complex involving at least two different components to act in concert. My laboratory has been using Y. enterocolitica and S. enteritidis as model systems to study entry of bacteria into eukaryotic cells. The long-term goals of our work are to understand the bacteria-host interaction at the molecular level, and to determine what the role of entry is in the pathogenesis of infections. For S. enteritidis we have been characterizing entry defective mutants. For Y. enterocolitica our work has focused on two genes, inv and ail, which encode proteins that can promote entry. The experiments described in this proposal are aimed at further characterizing these genes, their products, and their role in entry and pathogenesis. Specifically we propose to address the following questions: 1) How many S. enteritidis invasion genes are there and what are their products? 2) What is the effect of mutations affecting entry on the virulence of S. enteritidis? 3) What is the effect on virulence of mutations in inv and/or ail of Y. enterocolitica? 4) How does Ail promote invasion? An understanding of the process of bacterial invasion, should make it possible to devise better methods of treatment and prevention in the future.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Modified Research Career Development Award (K04)
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Bacteriology and Mycology Subcommittee 2 (BM)
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Washington University
Schools of Medicine
Saint Louis
United States
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Axler-Diperte, Grace L; Miller, Virginia L; Darwin, Andrew J (2006) YtxR, a conserved LysR-like regulator that induces expression of genes encoding a putative ADP-ribosyltransferase toxin homologue in Yersinia enterocolitica. J Bacteriol 188:8033-43
Miller, Virginia L (2002) Connections between transcriptional regulation and type III secretion? Curr Opin Microbiol 5:211-5
Darwin, A J; Miller, V L (2001) The psp locus of Yersinia enterocolitica is required for virulence and for growth in vitro when the Ysc type III secretion system is produced. Mol Microbiol 39:429-44
Schmiel, D H; Young, G M; Miller, V L (2000) The Yersinia enterocolitica phospholipase gene yplA is part of the flagellar regulon. J Bacteriol 182:2314-20
Badger, J L; Young, B M; Darwin, A J et al. (2000) Yersinia enterocolitica ClpB affects levels of invasin and motility. J Bacteriol 182:5563-71
Darwin, K H; Miller, V L (2000) The putative invasion protein chaperone SicA acts together with InvF to activate the expression of Salmonella typhimurium virulence genes. Mol Microbiol 35:949-60
Darwin, K H; Miller, V L (1999) InvF is required for expression of genes encoding proteins secreted by the SPI1 type III secretion apparatus in Salmonella typhimurium. J Bacteriol 181:4949-54
Young, G M; Smith, M J; Minnich, S A et al. (1999) The Yersinia enterocolitica motility master regulatory operon, flhDC, is required for flagellin production, swimming motility, and swarming motility. J Bacteriol 181:2823-33
Darwin, A J; Miller, V L (1999) Identification of Yersinia enterocolitica genes affecting survival in an animal host using signature-tagged transposon mutagenesis. Mol Microbiol 32:51-62
Young, G M; Schmiel, D H; Miller, V L (1999) A new pathway for the secretion of virulence factors by bacteria: the flagellar export apparatus functions as a protein-secretion system. Proc Natl Acad Sci U S A 96:6456-61

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