Dr Terry Kwok-Schuelein
BSc(Hons), PhD, Grad Cert Higher Ed
Tel: +61-3-9902 9216
Fax: +61-3-9905 3726
Office: Room 254, Level 2, Building 76 (STRIP)
Dr. Terry Kwok-Schuelein obtained her Ph.D. in 1998 from the University of Melbourne in Australia where she studied the structure and function of the Escherichia coli transcriptional regulatory protein TyrR. She carried out her post-doctoral study in the field of molecular pathogenesis and cellular microbiology at the Max Planck Institute of Infection Biology in Tuebingen, Germany. In 2003, she continued her post-doctoral research at Otto-von-Guericke University in Germany to further study the molecular basis of Helicobacter pylori infection. From 2006 to 2008, she was a senior research fellow at the University of Zürich in Switzerland focusing on antimicrobial drug discovery and RNA interference.
Our passion is to understand the molecular mechanisms by which microbes induce cancers using Helicobacter-associated stomach and liver cancers as primary model systems.
Our goal is to discover potential drug candidates to alleviate the burden of infections and infection-associated malignancies.
Understanding the Molecular Basis of How Chronic Microbial Infections Cause Cancer
Chronic microbial infections are increasingly recognised as an inducer of various types of cancer. At least 15% of malignancies worldwide are attributed to infections by viruses, bacteria, and other pathogens. A more thorough understanding of chronic infections and their causal relationship with cancer as well as the development of new therapeutics and diagnostic markers are of fundamental importance.
We use Helicobacter infections as model systems to identify the host receptors and signalling pathways involved in chronic bacterial infections, chronic inflammation and cancer. Helicobacter pylori (Hp) and Helicobacter hepaticus (Hh) are rod-shaped Gram-negative bacteria which colonise persistently in the human gastrointestinal tracts and liver, respectively. Hp and Hh are associated with adenocarcinoma in the stomach and liver, respectively. There has also been increasing evidence suggesting that Hp might be associated with hepatitis C cirrhosis and hepatocellular carcinoma.
The availability of well-established genetic tools and animal models in the field has made Helicobacter infection one of the most important model systems for understanding the biology of pathogen-induced cancers and the mechanisms by which chronic inflammation progresses to cancer.
A New Role of Integrins in Hp-induced Chronic Inflammation and Oncogenesis
Integrins are eukaryotic receptors which play key roles in cell adhesion, migration, inflammatory responses and carcinogenesis. They are also key players in signal transduction and important drug targets. We have recently identified a novel surface protein of Hp, CagL, which interacts with the integrin receptors on human stomach epithelial cells. CagL is a component of the Type IV secretion (T4S) apparatus, a major virulence factor of Hp which can be envisaged as a macromolecular machine gun that “shoots” virulence factor(s) into human gastric epithelial cells. Data suggest that the docking of CagL on the host integrin receptor might act as a trigger of the “shooting” processes. Understanding the precise mechanism by which the T4S process occurs and influences the host cell functions remains a major focus in the field.
Our Research Approaches
In collaboration with research teams in Australia, Germany and Switzerland, we aim to use a multi-disciplinary approach to understand the pathogenesis of Helicobacter-associated malignancies.
Our research aims to address the following key questions:
Which host receptors/components do Hp and Hh target in various cell types during chronic infection?
How does Helicobacter turn normal host cell signalling pathways into oncogenic cascades? How does Helicobacter, upon interaction with the host cells, alter normal host cell functions such as proliferation, migration and adhesion?
What are the implications of Hp CagL-mediated integrin signalling in primary gastric cells and 3-D gastric cell cultures?
Does the interaction of CagL with integrins play a role in other cell types such as liver cells and, as such, contribute to hepatocellular carcinoma?
Can some of the host or bacterial proteins identified as key players in the pathogenesis of Helicobacter infection be used as novel drug targets for the prevention of Helicobacter-related malignancies?
Our research is based on a multi-disciplinary approach, drawing on expertises in the areas of biochemistry, cell biology, microbiology and genetics. Techniques used include:
- Gene-knockdown in cell culture by RNAi
- 2D and 3D tissue culture models
- Knock-in and knock-out mice
- Cloning and mutagenesis
- Pull-down assays
- Gene expression analysis by real-time RT-PCR
- Western blots and immunoprecipitation
- Biacore analyse and other binding assays
- Protein purification
- Proteomics techniques including mass spectrometry, 1D and 2D SDS-PAGE
- Analytic gel filtration and analytical ultracentrifugation
- Confocal laser scanning microscopy
- Fluorescence live cell imaging
National Health and Medical Research Council of Australia
Our interdisciplinary approach is strongly supported by collaboration with research groups in Germany, Switzerland and within Australia.
1. Klionsky, D.J., Abdelmohsen, K., Abe, A., Abedin, M.J., Abeliovich, H., Acevedo Arozena, A., et al. (2016).
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1-222.
2. Tafreshi, M., Zwickel, N., Gorrell, R.J. and Kwok, T. (2015). Preservation of Helicobacter pylori CagA translocation and host cell proinflammatory responses in the face of CagL hypervariability at amino acid residues 58/59. PLoS One 10, e0133531.
3. Deen, N.S., Gong, L., Naderer, T., Devenish, R.J. and Kwok, T. (2015). Analysis of the relative contribution of phagocytosis, LC3-Associated phagocytosis, and canonical autophagy during Helicobacter pylori infection of macrophages. Helicobacter.
4. Pang, S.S., Nguyen, S.T.S., Perry, A.J., Day, C.J., Panjikar, S., Tiralongo, J., Whisstock, J. C.
Kwok, T. (2014). The three-dimensional structure of the extracellular adhesion domain of the sialic acid-binding adhesin SabA from Helicobacter pylori. J Biol Chem 289, 6332-6340.
5. Yadegar, A., Mobarez, A.M., Alebouyeh, M., Mirzaei, T., Kwok, T. and Zali, M.R. (2014). Clinical relevance of cagL gene and virulence genotypes with disease outcomes in a Helicobacter pylori infected population from Iran. World J Microbiol Biotechnol 30, 2481-2490.
6. Deen, N.S., Huang, S.J., Gong, L., Kwok, T*. and Devenish, R.J. (2013). The impact of autophagic processes on the intracellular fate of Helicobacter pylori: More tricks from an enigmatic pathogen? Autophagy 9, 639-652. *Co-senior author.
7. Gorrell, R.J., Wijburg, O.L., Pedersen, J.S., Walduck, A.K., Kwok, T., Strugnell, R.A. and Robins-Browne, R.M. (2013). Contribution of secretory antibodies to intestinal mucosal immunity against Helicobacter pylori. Infect Immun 81, 3880-3893.
8. Woon, A., Tohidpour, A., Alonson, H., Saijo-Hamano, Y., Kwok, T. and Roujeinikova, A. (2013). Conformational analysis of isolated domains of Helicobacter pylori CagA. PLoS One 8, e79367.
9. Gorrell, R.J., Guan, J., Xin, Y., Tafreshi, M.A., Hutton, M.L., McGuckin, M.A., Ferrero, R. L., Kwok, T. (2013). A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by the Helicobacter pylori type IV secretion system. Cell Microbiol. 5:554-570.
10. Celik, N., Webb, C.T., Leyton, D.L., Holt, K.E., Heinz, E., Gorrell, R., Kwok, T., Naderer, T., Strugnell, R. A., Speed, T. P., Teasdale, R. D., Likic, V. A., Lithgow, T. (2012). A bioinformatic strategy for the detection, classification and analysis of bacterial autotransporters. PLoS One 7, e43245
11. Palframan, S.L., Kwok, T. and Gabriel, K. (2012). Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis. Front.Cell.Inf.Microbio. 2, DOI: 10.3389/fcimb.2012.00092
12. Srikhanta, Y.N., Gorrell, R.J., Steen, J.A., Gawthorne, J.A., Kwok, T., Grimmond, S.M., et al. (2011). Phasevarion mediated epigenetic gene regulation in Helicobacter pylori. PLoS One 6, e27569
13. Schuelein, R., Everingham, P. and Kwok, T. (2011) Integrin-mediated type IV secretion by Helicobacter: what makes it tick? Trends in Microbiol. 19:211-216
14. Hutton, M. L., Kaparakis-Liaskos, M.,Turner, L., Cardona, A., Kwok, T., Ferrero, R. L. (2010) Helicobacter pylori exploits cholesterol-rich microdomains for induction of NF-kB-dependent responses and peptidoglycan delivery in epithelial cells. Infect. Immun. 78: 4523-4531
15. Foo, J. H., J. G. Culvenor, R. L. Ferrero, T. Kwok, T. Lithgow, and K. Gabriel. (2010) Both the p33 and p55 subunits of the Helicobacter pylori VacA toxin are targeted to mammalian mitochondria. J Mol Biol 401:792-798
16. Kwok, T., H. Helfer, M. I. Alam, J. Heinrich, J. Pavlovic, and K. Moelling. (2009) Inhibition of influenza A virus replication by short double-stranded oligodeoxynucleotides. Arch Virol 154:109-114
17. Kwok, T., J. Heinrich, J. Jung-Shiu, M. G. Meier, S. Mathur, and K. Moelling. (2009) Reduction of gene expression by a hairpin-loop structured oligodeoxynucleotide: alternative to siRNA and antisense. Biochim Biophys Acta 1790:1170-1178
18. Kwok, T., Zabler, D., Urman, S., Rohde, M., Hartig, R, Wessler, S., Misselwitz, R., Berger, J., Sewald, N., König, W., Backert, S. (2007) Helicobacter exploits integrin for type IV secretion and kinase activation. Nature. 449:862-866
19. Verger, D., Carr, P.D., Kwok, T., Ollis, D.L. (2007) Crystal structure of the N-terminal domain of the TyrR transcription factor responsible for gene regulation of aromatic amino acid biosynthesis and transport in Escherichia coli K12. J Mol Biol. 367:102-112
20. Moelling K., Matskevich A., Elzaouk, L., Heinrich, J., Jung J.S., Kwok T. and Mathur S. (2007) Self-inactivation of HIV by its own RT/RNase H. Retrovirology. 3:S57
21. Brandt, S., *Kwok, T., Hartig, R., Konig, W., Backert, S. (2005) NF-kB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proc Natl Acad Sci U S A. 102(26):9300-9305. *Shared first-authorship
22. Backert, S., Kwok, T., Schmid, M., Selbach, M., Moese, S., Peek, R.M. Jr, Konig, W., Meyer TF, Jungblut PR. (2005) Subproteomes of soluble and structure-bound Helicobacter pylori proteins analyzed by two-dimensional gel electrophoresis and mass spectrometry. Proteomics 5(5):1331-1345
23. Backert, S., Gressmann, H., Kwok, T., Zimny-Arndt, U., Konig, W., Jungblut, P.R., Meyer T.F. (2005) Gene expression and protein profiling of AGS gastric epithelial cells upon infection with Helicobacter pylori. Proteomics 5: 3902-3918
24. Kwok, T., König, W., Backert, S. (2005) Invasion of Helicobacter pylori into gastric epithelial cells: a potential determinant of virulence, persistence and treatment failures. International Journal of Medical Microbiology. 295: 130
25. Backert S, Kwok T, Konig W. (2005) Conjugative plasmid DNA transfer in Helicobacter pylori mediated by chromosomally encoded relaxase and TraG-like proteins. Microbiology. 11: 3493-3503
26. König, W., Lauf H., Arnold, U., Tammer, I., Ghebremedhin, B., Clarici A., Thies, F., Drynda A., Schmalcz, A., Kwok, T., Arnold, R., Backert, S., Werchau, H. and König, B. (2005). Natürliche und adaptive Immunität des Respirationstraktes - Bedeutung mikrobieller Faktoren für Infektabwehr und Sensibilisierung. Atemw. Lungenkrkh. 31 (4): 188-203
27. Moese, S., Selbach, M., Kwok, T. et al. (2004) Helicobacter pylori induces AGS cell motility and elongation via independent pathways. Infection and Immunity 72:3646-3649
28. Backert, S., Schwarz, T., Miehlke, S., Sommer, Ch., Kirsch, C., Kwok, T. et al. (2004) Function of the cag pathogenicity island in Helicobacter pylori isolated from patients with gastritis, peptic ulcer and gastric cancer. Infection and Immunity 72:1043-1056
29. Kwok T., Backert S., Schwarz H., Berger J., Meyer T.F. (2002) Specific entry of Helicobacter pylori into cultured gastric epithelial cells via a zipper-like mechanism. Infection and Immunity 70:2108-2120
1 Postdoctoral Position
1 Research Assistant Position
2 PhD Positions
1-2 Honours Position(s)
Postdoctoral Research Fellow
We are seeking a talented and enthusiastic scientist to join the research group as a Postdoctoral Research Fellow to work in the exciting and fast-growing areas of microbial carcinogenesis. The successful candidate will develop molecular and cell-based assays to study the molecular and cellular mechanisms by which Helicobacter causes cancer.
The candidate should have a Ph.D. in Biochemistry or Cell Biology. Strong background in cancer-related signal transduction, receptor biochemistry, angiogenesis, primary cell culture and/or 3-D cell culture would be advantageous. Experience in stem cell research would be an asset. If you are interested in applying your expertise to explore the exciting world of bacteria-host interactions and infectious cancer biology, you are most welcome to contact me for discussion of the available projects or new project ideas. International applicants are welcome. Attractive top-up salary will be offered to awardees of Australian or international postdoctoral fellowships.
Duration: 12 months, extendable up to 36 months
Application: Candidates should forward their CV, a cover letter and contact details of 3 referees to email@example.com
PhD postgraduate scholarships with an annual stipend of $20,007 (tax-free) are available for Australian citizens or permanent residents with a H1 or H2A Honours degree.
The PhD projects available provide excellent training opportunities for PhD candidates to develop solid skills and knowledge in the fields of bacterial pathogenesis, cancer biology and biology of chronic inflammatory diseases. Candidates will have the unique advantage to work at the interface of prokaryotic and eukaryotic biology, developing skill in a large variety of fundamental techniques such as RNAi, eukaryotic cell culture, live cell imaging, confocal laser scanning microscopy, immunofluorescence staining, Western blotting, ELISA, protein purification, protein-interaction analyses, mutagenesis, bacterial culture, etc. Someone who is enthusiastic in exploring the exciting world of bacteria-host interactions and infectious cancer biology is most welcome to contact me for further discussion of the projects.
Application*: Please forward a brief CV, academic transcripts and contact details of 3 referees to firstname.lastname@example.org
Honours projects are available in our lab which enable the candidate to develop skills and knowledge in eukaryotic cell culture techniques, fundamental microbiological techniques including mutagenesis and bacterial culture, RNAi, immunostaining, Western blotting, ELISA, confocal laser scanning microscopy, live cell imaging, etc. Someone who is enthusiastic in learning about the exciting secrets of bacterial pathogenesis, bacteria-host interactions and infectious cancer biology is most welcome to apply.
Application: Please forward a brief CV, academic transcripts and contact details of at least 2 referees to email@example.com
Our lab is located on the second floor in building 76 as part of the modern Science Technology Research and Innovation Precinct (STRIP). The precinct is equipped with the state-of-the-art facilities including: