Project: Cellular small GTPase regulation and subversion by intracellular bacterial pathogens
University of Cambridge
Tennis Court Road
Salmonella enterica serovar Typhi (S.Typhi) and Typhimurium (S.Typhimurium) are bacterial pathogens of global importance causing 27 million and 94 million infections every year, respectively. Infections caused by the related pathogens result in distinct diseases. S.Typhi, a strict human pathogen, causes a debilitating systemic disease known as typhoid fever while S.Typhimurium infects a range of animal hosts and generates a self-limiting gastroenteritis in humans.
To cause disease both pathogens must establish intracellular infections, which is achieved by bacterial delivery of virulence ‘effector’ proteins into target host epithelial cells that hijack master regulators of cellular functions known as Ras family small GTPases (e.g. Rho, Arf and Rab GTPases). By manipulating Rho and Arf GTPases that control the host cell’s actin cytoskeleton, Salmonella (labelled in red in figure) are able to remodel the host cell surface plasma membrane (labelled in green) and trigger their own uptake into the cell where they reside intracellularly within Salmonella-containing vacuoles (SCVs, shown in magnified box). Salmonella effectors manipulate Rab GTPases, which control vesicular transport pathways, to ensure that the pathogen counteracts the action of bacteriocidal lysosomes and can replicate within SCVs.
The project combines protein biochemistry and cell biology approaches to solve how virulence effectors subvert small GTPase pathways, which will illuminate virulence mechanisms underlying disease while uncovering important new cell biology governing the actin cytoskeleton and vesicular transport.
- Humphreys, D., Davidson, A.C, Hume, P.J., Makin, L.E., Koronakis, V. (2013) Arf6 coordinates actin assembly through the WAVE complex, a mechanism usurped by Salmonella to invade host cells. Proceedings of the National Academy of Sciences of the United States of America. 110(42):16880-16885.
- Humphreys, D., Liu, T., Davidson, A.C., Hume, P.J., and Koronakis, V. (2012) Drosophila Arf1 homologue Arf79F is essential for lamellipodia formation. Journal of Cell Science 125, 5621-5629
- Humphreys, D., Davidson, A.C., Hume PJ, Koronakis, V. (2012) Salmonella SopE and host GEF ARNO cooperate to recruit and activate WAVE to trigger bacterial invasion. Cell Host & Microbe 11, 129-39
- Koronakis, V., Hume, P.J., Humphreys, D., Liu, T., Horning, O., Jensen, O.N, McGhie, E.J. (2011) WAVE regulatory complex activation by cooperating GTPases Arf and Rac1. Proceedings of the National Academy of Sciences of the United States of America 108(35):14449-54.
- Smith, K., Humphreys, D., Hume, P.J., and Koronakis, V. (2010) Enteropathogenic Escherichia coli recruits the cellular inositol phosphatase SHIP2 to regulate actin-pedestal formation. Cell Host & Microbe 7, 13-24