monella enterica serovar Typhimurium is a common cause of gastroenteritis. Virulence is determined by five Salmonella Pathogenicity Islands (SPI) encoded on the bacterial chromosome. SPI1 and SPI2 encode the structural components of two Type Three Secretion Sytems (TTSS) that translocate effectors into the host cell. The SPI1 effector SigD is an inositol phosphatase that induces the activation of Akt/PKB a mammalian serine threonine kinase. The role of Akt activation in pathogenesis remains unclear, however, in cultured epithelial cells it appears to be involved in preventing the onset of apoptosis in infected cells. More specifically we have found that a sigD deletion mutant induces Caspase 3 activation compared to wild type. This may be important for the survival and replication of intracellular bacteria. In macrophages activation of Akt by Salmonella is more complex since lipopolysaccharide will activate the kinase in the absence of SigD. Comparison of the two pathways has revealed important differences. In particular, SigD-mediated activation is insensitive to Wortmannin a well described inhibitor of Akt activation via phosphatidylinositol-3-kinase. Thus SigD-dependent Akt activation appears to occur via a novel pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000909-01
Application #
6669972
Study Section
(LICP)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Steele-Mortimer, Olivia (2008) The Salmonella-containing vacuole: moving with the times. Curr Opin Microbiol 11:38-45
Drecktrah, Dan; Knodler, Leigh A; Howe, Dale et al. (2007) Salmonella trafficking is defined by continuous dynamic interactions with the endolysosomal system. Traffic 8:212-25
Knodler, Leigh A; Bertero, Michela; Yip, Calvin et al. (2006) Structure-based mutagenesis of SigE verifies the importance of hydrophobic and electrostatic residues in type III chaperone function. Mol Microbiol 62:928-40
Drecktrah, Dan; Knodler, Leigh A; Ireland, Robin et al. (2006) The mechanism of Salmonella entry determines the vacuolar environment and intracellular gene expression. Traffic 7:39-51
Henry, Thomas; Couillault, Carole; Rockenfeller, Patrick et al. (2006) The Salmonella effector protein PipB2 is a linker for kinesin-1. Proc Natl Acad Sci U S A 103:13497-502
Magalhaes, Ana Cristina; Baron, Gerald S; Lee, Kil Sun et al. (2005) Uptake and neuritic transport of scrapie prion protein coincident with infection of neuronal cells. J Neurosci 25:5207-16
Knodler, Leigh A; Bestor, Aaron; Ma, Caixia et al. (2005) Cloning vectors and fluorescent proteins can significantly inhibit Salmonella enterica virulence in both epithelial cells and macrophages: implications for bacterial pathogenesis studies. Infect Immun 73:7027-31
Knodler, Leigh A; Steele-Mortimer, Olivia (2005) The Salmonella effector PipB2 affects late endosome/lysosome distribution to mediate Sif extension. Mol Biol Cell 16:4108-23
Knodler, Leigh A; Finlay, B Brett; Steele-Mortimer, Olivia (2005) The Salmonella effector protein SopB protects epithelial cells from apoptosis by sustained activation of Akt. J Biol Chem 280:9058-64
Nelson, David E; Virok, Dezso P; Wood, Heidi et al. (2005) Chlamydial IFN-gamma immune evasion is linked to host infection tropism. Proc Natl Acad Sci U S A 102:10658-63

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