About the Project
The Ply protein forms large pores (25nm diameter) in cell membranes and alters a range of host cell functions including immune response, macrophage function and the permeability of epithelial and endothelial cell barriers. These later effects are important in the ability of the bacterium to cross from lung into blood and from blood into brain (4, 5). The human pathogen Staphylococcus aureus also makes a pore forming protein termed alpha-haemolysin which forms small pores (2nm diameter) in eukaryotic cell membranes. PLY and Staphylococcus haemolysin will be used to evaluate the effects of membrane pore size (large vs small) on the cell biology of both epithelial and endothelial cell barriers. Both Ply and staphylococcal alpha toxin alter the permeability of epithelial and endothelial cell barriers by activation of disintegrin and metalloprotease-10 (ADAM-10). ADAM-10 degrades cell junction proteins such as E-Cadherin and leads to protein ‘shedding’ from the cells. The activity of ADAM-10 is controlled by membrane bound tetraspanin-15 (6, 7). The hypothesis is that pore forming proteins produced by these bacterial pathogens activate Tspan15/ADAM-10 and lead to changes in barrier permeability, shedding of cell surface markers and bacterial invasion of the lung and brain during infection. As one of the proteins shed by the epithelium due to activation of ADAM-10 is E-Cadherin which is also a receptor for a cell surface protein of Streptococcus pneumoniae (2), it is possible that cleavage will affect bacterial binding to cells and may lead to invading bacteria being coated with cleaved E-Cadherin. It is also possible that production of pore forming toxin by one species of bacteria reduces the ability of the other species to bind due to receptor shedding.
Applicants should have a strong background in molecular microbiology and eukaryotic cell biology They should have a commitment to infectious disease research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in microbiology or biochemistry.
2. Anderton JM, Rajam G, Romero-Steiner S, Summer S, Kowalczyk AP, Carlone GM, Sampson JS, Ades EW. 2007. E-cadherin is a receptor for the common protein pneumococcal surface adhesin A (PsaA) of Streptococcus pneumoniae. Microb Pathog 42: 225-36
3. Surve MV, Bhutda S, Datey A, Anil A, Rawat S, Pushpakaran A, Singh D, Kim KS, Chakravortty D, Banerjee A. 2018. Heterogeneity in pneumolysin expression governs the fate of Streptococcus pneumoniae during blood-brain barrier trafficking. PLoS Pathog 14: e1007168
4. Gutbier B, Schonrock SM, Ehrler C, Haberberger R, Dietert K, Gruber AD, Kummer W, Michalick L, Kuebler WM, Hocke AC, Szymanski K, Letsiou E, Luth A, Schumacher F, Kleuser B, Mitchell TJ, Bertrams W, Schmeck B, Treue D, Klauschen F, Bauer TT, Tonnies M, Weissmann N, Hippenstiel S, Suttorp N, Witzenrath M, Group CS. 2018. Sphingosine Kinase 1 Regulates Inflammation and Contributes to Acute Lung Injury in Pneumococcal Pneumonia via the Sphingosine-1-Phosphate Receptor 2. Crit Care Med 46: e258-e67
5. Zysk G, Schneider-Wald BK, Hwang JH, Bejo L, Kim KS, Mitchell TJ, Hakenbeck R, Heinz H-P. 2001. Pneumolysin Is the Main Inducer of Cytotoxicity to Brain Microvascular Endothelial Cells Caused by Streptococcus pneumoniae. Infect. Immun. 69: 845-52
6. Tomlinson MG. 2017. Eye-Opening Potential for Tetraspanin Tspan12 as a Therapeutic Target for Diseases of the Retinal Vasculature. Circulation 136: 196-9
7. Inoshima I, Inoshima N, Wilke GA, Powers ME, Frank KM, Wang Y, Bubeck Wardenburg J. 2011. A Staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat Med 17: 1310-4
8. Seipold L, Altmeppen H, Koudelka T, Tholey A, Kasparek P, Sedlacek R, Schweizer M, Bar J, Mikhaylova M, Glatzel M, Saftig P. 2018. In vivo regulation of the A disintegrin and metalloproteinase 10 (ADAM10) by the tetraspanin 15. Cell Mol Life Sci 75(17), 3251-3
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