Major Areas of Research
- Host-cell proteins involved in invasion
- Biogenesis of the Salmonella-containing vacuole
Salmonella enterica serovar Typhimurium (S. Typhimurium) is a common cause of gastroenteritis in humans. Our group studies how S. Typhimurium interacts with mammalian cells. This facultative intracellular pathogen uses two type-three secretion systems (T3SS) to deliver bacterial effector proteins into the host cell. T3SS1 mediates invasion of nonphagocytic cells and early post-invasion events. In contrast, T3SS2 is induced following invasion and is required for survival and replication within the Salmonella-containing vacuole (SCV).
Host Cell Proteins Involved in Invasion
T3SS1 is also known as the invasion-associated T3SS because it is essential for invasion of non-phagocytic cells. Multiple T3SS1 effector proteins target the actin cytoskeleton, directly or indirectly, to induce localized membrane ruffles on the cell surface. However, T3SS1 effectors are also important for early SCV biogenesis and other post-invasion processes. We are studying the role of the inositol phosphatase SopB, a T3SS1 effector that participates in invasion and early biogenesis of the SCV. In epithelial cells, SopB also stimulates phosphorylation and activation of the pro-survival kinase Akt via an indirect process that is not well understood. We are investigating the consequences of Akt activation in the context of Salmonella invasion, as this important kinase has many substrates and affects several essential cellular processes.
Biogenesis of the SCV
In epithelial cells, Salmonella can replicate within the membrane bound SCV or within the cytosol. Biogenesis of the SCV involves early interactions with the endocytic pathway followed by delivery of lysosomal membrane proteins and is dependent on both T3SS. We have used live cell imaging techniques to reveal the dynamic interactions that occur between the SCV and endosomes and lysosomes. More recently, we have used this same approach to investigate the bimodal lifestyle of intracellular Salmonella. These studies have shown that replication in the cytosol occurs more rapidly than in the SCV, at least in epithelial cells.
Dr. Steele-Mortimer received her Ph.D. in cell biology from the European Molecular Biology Laboratory in 1994. From 1995 to 1999, she did postdoctoral research on Salmonella-host cell interactions in the laboratory of B. Brett Finlay at the University of British Columbia in Vancouver, followed by one year at Washington University, St. Louis, with Phillip D. Stahl. She came to the National Institutes of Health in 2001 and became a tenured senior investigator in 2007. Dr. Steele-Mortimer is an associate editor ofMicrobial Pathogenesis and is a member of the editorial board of Traffic.
Carrie Jolly, Stephanie Lathrop, Ciaran Finn, Seth Winfree, Tregei Starr
Malik-Kale P, Winfree S, Steele-Mortimer O. The bimodal lifestyle of intracellular salmonella in epithelial cells: replication in the cytosol obscures defects in vacuolar replication. PLoS ONE. 2012;7(6):e38732.
Cooper KG, Winfree S, Malik-Kale P, Jolly C, Ireland R, Knodler LA, Steele-Mortimer O. Activation of Akt by the bacterial inositol phosphatase, SopB, is wortmannin insensitive. PLoS ONE. 2011;6(7):e22260.
Knodler LA, Ibarra JA, Pérez-Rueda E, Yip CK, Steele-Mortimer O. Coiled-coil domains enhance the membrane association ofSalmonella type III effectors. Cell Microbiol. 2011 Oct;13(10):1497-517.
Knodler LA, Vallance BA, Celli J, Winfree S, Hansen B, Montero M, Steele-Mortimer O. Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia. Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17733-8.
Ibarra JA, Knodler LA, Sturdevant DE, Virtaneva K, Carmody AB, Fischer ER, Porcella SF, Steele-Mortimer O. Induction ofSalmonella pathogenicity island 1 under different growth conditions can affect Salmonella-host cell interactions in vitro.Microbiology. 2010 Apr;156(Pt 4):1120-33.