Salmonella enterica serovar Typhimurium is a common cause of enterocolitis in humans and cattle but causes a systemic, typhoid-like, disease in susceptible mice. Pathogenesis of this facultative intracellular pathogen is dependent on the ability to invade non-phagocytic cells, such as those found in the intestinal epithelium. Invasion is dependent on a type III secretion system (T3SS1), which is used to translocate a set of bacterial effector proteins into the host cell. Following internalization intracellular Salmonella survive and replicate within a modified phagosome, the Salmonella-containing vacuole (SCV). A second type III system (T3SS2) is induced intracellularly and is associated with intracellular survival/replication and biogenesis of the SCV. To understand Salmonella pathogenesis we must dissect the roles of the individual T3SS1 and T3SS2 effector proteins as well as the mechanisms that control their expression and activity inside host cells. Another important aspect of the host-pathogen interaction is the biogenesis of the SCV. A widely held belief, based on work from several labs, is that Salmonella prevent SCV-lysosome fusion and that this is an important requisite for intracellular survival and replication. We have shown that, contrary to this dogma, SCV biogenesis involves sustained dynamic interactions with the endocytic pathway including late endosomes and lysosome. We have now extended this work to show that Salmonella induced tubules, known as Sifs, are highly dynamic and exhibit bi-directional, microtubule-dependent movement. Furthermore, we demonstrated that endosomal content is delivered to Sifs by direct fusion events. We also published a collaborative study revealing new aspects of virulence gene expression, specifically of the regulons that encode T3SS1 and T3SS2.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
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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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