My laboratory is interested in extracellular protein secretion as it is one of the primary virulence mechanisms in bacterial infection. In gram-negative pathogens, many virulence factors are secreted via the type II secretion (T2S) pathway, a pathway common to Vibrio cholerae, Escherichia coli O157, Pseudomonas aeruginosa and Legionella pneumophila. The secreted substrates include toxins and degradative enzymes such as proteases and lipases. T2S mutants of V. cholerae and E. coli O157:H7 display a reduction in colonization efficiency in the gastrointestinal tract of mice and inactivation of the T2S system in Yersinia enterocolitica O:8 reduces its ability to spread to internal organs following intestinal colonization. The T2S system has also been shown to contribute to lung infections caused by the opportunistic pathogens P. aeruginosa and Legionella pneumophila. In addition, we have recently found that the T2S system supports the in vivo survival of Acinetobacter baumannii, an increasingly common nosocomial pathogen that primarily causes pneumonia and wound infections that can lead to severe blood stream infections.
My lab focuses on three main areas of research. We subject the T2S system to structure-function analysis to determine the mechanism of T2S. We identify extracellular proteins that are secreted by the T2S system and investigate their roles in in vivo and in vitro survival of V. cholerae and A. baumannii. In addition, we perform high throughput screening of small molecule inhibitors of T2S. This basic-translational research will generate new tools to be used to study the mechanism of T2S. They will also be exploited for the development of alternatives to antibiotics to combat multi-drug resistant gram-negative pathogens.
Johnson, T.L., Fong, J.C., Rule, C., Rogers, A., Yildiz, F.H., and Sandkvist, M. The Type II secretion system delivers matrix proteins for biofilm formation by Vibrio cholerae. J. Bacteriol., 196:4245-4252, 2014.
Korotkov, K.V., Sandkvist, M., and Hol, W.G.J. 2012. The type II secretion system: biogenesis, molecular architecture and mechanism. Nature Review Microbiology, 10:336-351.
Sikora A.E., Zielke, R., Lawrence, D.A., Andrews, P., and Sandkvist, M. 2011. Proteomic analysis of the Vibrio cholerae type II secretome reveals new proteins including three related serine proteases. J. Biol. Chem., 286:16555-16566.