Professor Sheila Nathan from the School of Biosciences and Biotechnology of Universiti Kebangsaan Malaysia (UKM) is truly a molecular biologist. She uses a diverse array of techniques at the molecular level to dissect the host-pathogen interaction for melioidosis. Melioidosis is a disease caused by a tropical pathogen, Burkholderia pseudomallei (formerly known as Pseudomonas pseudomallei). Prof. Nathan is also the Director of the Comparative Genomics and Genetics Research Centre at the Malaysia Genome Institute (GENOM Malaysia). Recently, Dr Valerie Soo from the SciMy team asked Prof. Nathan five questions about her research and beyond doubt, her answers reflect a life-long passion for science.
Q1. How did, or what made, you get into science?
It was a general interest in disease and trying to understand the mechanisms of disease and cancer. The undergraduate Biochemistry programme at the Faculty of Life Sciences (as it was known then) of UKM was also instrumental in instilling an even deeper interest in the biochemistry of disease, cancer and the human system. The ability to work in a laboratory and to explore unknown territory leading to new clues and answers eventually set my path towards an MSc and DPhil in the UK.
Q2. You seem to have a broad interest in unravelling the molecular mechanisms that underlie microbial infections. Can you tell us more about your research?
My DPhil training at the Trafford Centre for Medical Research (University of Sussex) was on DNA repair, specifically on gene-specific repair in UV-induced disorders. This project involved the use of a number of molecular biology-based approaches to solve the issue in hand, and the opportunities to work in collaborating labs in the Netherlands.
Upon my return to UKM, it was evident that the local research scenario did not encourage pursuing research on DNA repair — which was understandable — as it was not a critical problem in Malaysia. In lieu of this, I joined the research group in UKM working on B. pseudomallei. This is a very intriguing pathogen in the sense that not very much was known about its mechanism of pathogenesis at that time. Unfortunately, this lack of understanding remains a bottleneck today. The research group in UKM was then investigating the potential presence and role of an exotoxin from B. pseudomallei, and I was responsible for producing and characterising monoclonal antibodies for this protein. Furthermore, we were able to produce recombinant antibodies with partial neutralization properties using phage display technology. We extended the use of this technology to the construction and characterisation of recombinant antibodies against the protease protein secreted by the same pathogen. These antibodies were constructed during my sabbatical at the Scripps Research Institute in California.
In 2005, I was invited to initiate a collaborative research project with the Department of Genetics, Stanford University (USA) on investigating the host-pathogen relationship of B. pseudomallei using the host model Caenorhabditis elegans. The C. elegans Research Facility was established in UKM and it was the first C. elegans-associated lab in Malaysia. Together with the co-investigator, Dr. Man-Wah Tan from Stanford University, we were able to demonstrate that continuous exposure to live pathogen is critical for host killing1 . Further expression profiling studies have also demonstrated for the first time that B. pseudomallei is able to degrade or inactivate transcription factors that have critical roles in inducing immune response gene expression, hence allowing the bacterium to circumvent the host immune system. We were able to show similar inactivation or delay in the immune response using a mouse model of melioidosis, and a diabetic mouse model2, 3 . Looking at the mechanism of pathogenesis from the pathogen’s perspective, we were also able to profile expression changes in bacterial gene expression immediately upon infection of macrophage cells4.
Our findings have intimated the ability of the bacterium to either up- or down-regulate its essential genes in order to escape recognition by host receptors during the invasion process, as well as to acclimatise itself to the intracellular environment of the host. In another collaboration with the University of Sheffield, UK, we have reported on the presence and three-dimensional structure of a potent B. pseudomallei toxin5 . We further provided evidence of the toxin interaction with its human target, leading to inhibition of protein synthesis and eventual cell death.
Other work has also identified immunogenic antigens that have been evaluated as potential vaccine and diagnostic candidates6-9 . This has led to a number of patents being filed and granted locally as well as internationally.
Q3. In which direction do you foresee your research is heading?
There is still a vast amount of information on B. pseudomallei that has yet to be unearthed in terms of its pathogenesis as well as the host response towards its infection. This bacterium is unlike many other pathogens, and has only succeeded in confounding those working on B. pseudomallei and its closely related family members. This has culminated in the lack of a proper drug regimen, as well as rapid and effective diagnostics, although the international group of researchers working on B. pseudomallei is growing.
|MELIOIDOSIS: THE MYSTERIOUS KILLER DISEASE
Melioidosis is an infectious disease caused by Burkholderia pseudomallei, a bacteria that lives in the soil and water. Melioidosis usually affects those who are immuno-compromised, especially diabetics.
Known as ‘the poor man’s disease’, another risk factor for melioidosis is occupational exposure, particularly farmers and field workers who are constantly exposed to muddy and stagnant water in rice-farming areas, cleared fields, cultivated and irrigated sites, as well as drains and ditches.
Melioidosis is a serious disease of humans and animals that occurs primarily in Southeast Asia (Malaysia, Thailand, and Myanmar), North Australia and other tropical areas. It is thought that 10-25% of people in endemic areas may be infected but remain asymptomatic. In Malaysia, 50% of its citizens are seropositive and this disease poses a serious threat because the symptoms are not straightforward, and it is often misdiagnosed due to its similarity with other diseases.
SYMPTOMS OF MELIOIDOSIS
We are currently using various high-end approaches that are reliant on both laboratory experiments, as well as in silico analyses to identify as many virulence factors produced by this bacterium that appear to cause a diverse range of symptoms in different individuals. Broad plasticity is also apparent among different isolates of the same species at the genome level, which makes the identification of species-specific virulence molecules (that would aid in the development of drugs and vaccines) more tedious. In terms of how our current and future research findings can be translated into biotechnological applications, the immediate scope would be in diagnostics and vaccinology. Diagnosis of melioidosis is currently reliant on bacterial culture and its identification as the gold standard used in reference laboratories and clinical settings. This diagnostic method requires contained facilities, trained personnel and an extended length of time. Treatment for melioidosis is antibiotics-dependent; however, an increasing rate of antibiotic resistance has been observed. The use of individual proteins as vaccine candidates fails to provide complete protection while disease manifestation is multi-factorial. Hence, this has called for urgent identifications of all potential virulence molecules in the quest to design the most effective vaccine, particularly for the most susceptible population.
Q4. What do you consider to be the highlight of your career so far?
I would have to say that it is a combination of graduating my first student, publishing a piece of work that is deemed as a scientific breakthrough and getting appointed as a full professor. Yet, in particular, the most prominent highlight is the excellence of my PhD and MSc students who have graduated from my research group. This is reflected by the BSc and MSc graduates being accepted into prestigious international universities to pursue their doctoral degrees [e.g. University of Sheffield and University of Bristol (UK), Stowers Institute (USA), NUS and NTU (Singapore)], as well as the PhD graduates acquiring postdoctoral positions in international research groups based in the USA (NIH, UC Berkeley, University of Georgia), UK (University of London) and Europe.
Q5. What bit of research has caught your eye recently? Why?
I would probably have to say “bacteria and the evolution of pathogenesis”. Whilst this is not new in terms of the research being carried out, there is an insatiable desire to understand why a harmless soil-dwelling bacterium decides to turn nasty once it has found its way into a completely different environment, even though, genotypically, it is still the same organism. If bacteriologists succeed in dissecting this enigma, we could be more successful in predicting or preventing disease, and of course, in the development of new drug therapies.
Prof. Nathan can be contacted at [email protected] for more information on her research.
 Lee, S. H., Ooi, S. k., Mahadi, N. M., Tan, M. W. and Nathan, S. (2011) Complete killing of Caenorhabditis elegans by Burkholderia pseudomallei is dependent on prolonged direct association with the viable pathogen. PLoS One. 6, e16707.
 Chin, C. Y., Monack, D. M. and Nathan, S. (2012) Delayed activation of host innate immune pathways in streptozotocin-induced diabetic hosts leads to more severe disease during infection with Burkholderia pseudomallei. Immunology. 135, 312-332.
 Chin, C. Y., Monack, D. M. and Nathan, S. (2010) Genome wide transcriptome profiling of a murine acute melioidosis model reveals new insights into how Burkholderia pseudomallei overcomes host innate immunity. BMC Genomics. 11, 672.
 Chieng, S., Carreto, L. and Nathan, S. (2012) Burkholderia pseudomallei transcriptional adaptation in macrophages. BMC Genomics. 13, 328.
 Cruz-Migoni, A., Hautbergue, G. M., Artymiuk, P. J., Baker, P. J., Bokori-Brown, M., Chang, C. T., Dickman, M. J., Essex-Lopresti, A., Harding, S. V., Mahadi, N. M., Marshall, L. E., Mobbs, G. W., Mohamed, R., Nathan, S., Ngugi, S. A., Ong, C., Ooi, W. F., Partridge, L. J., Phillips, H. L., Raih, M. F., Ruzheinikov, S., Sarkar-Tyson, M., Sedelnikova, S. E., Smither, S. J., Tan, P., Titball, R. W., Wilson, S. A. and Rice, D. W. (2011) A Burkholderia pseudomallei toxin inhibits helicase activity of translation factor eIF4A. Science. 334, 821-824.
 Su, Y. C., Wan, k. L., Mohamed, R. and Nathan, S. (2008) A genome level survey of Burkholderia pseudomallei immunome expressed during human infection. Microbes Infect. 10, 1335-1345.
 Hara, Y., Mohamed, R. and Nathan, S. (2009) Immunogenic Burkholderia pseudomallei outer membrane proteins as potential candidate vaccine targets. PLoS One. 4, e6496.
 Su, Y. C., Wan, k. L., Mohamed, R. and Nathan, S. (2010) Immunization with the recombinant Burkholderia pseudomallei outer membrane protein Omp85 induces protective immunity in mice. Vaccine. 28, 5005-5011.
 Chin, C. Y., Tan, S.-C. and Nathan, S. (2012) Immunogenic recombinant Burkholderia pseudomallei MprA serine protease elicits protective immunity in mice. Front. Cell. Inf. Microbio., 2:85.