Our Research Projects
Improved understanding of TB
To control TB through the development of new vaccines, drugs and diagnostic tests, we must first understand the microbe and how it causes disease.
To address the current gaps in knowledge, Centenary's TB researchers are focused on identifying the genetic armoury of the TB bacteria that allows it to replicate within the host and cause disease. Additionally we are concerned how the bacterium survives within the host for the life of the host, usually without causing any symptoms at all.
We are also committed to understanding the disease process from a bacterial prospective. We endeavour to identify the gene set required to: invade the lung, spread to other organs and establish a life-long chronic infection.
Mutant library
Importantly, we have developed a comprehensive TB bacteria mutant library with more than 15,000 individual, single gene mutants. This is one of the largest libraries in the world. This library is a valuable resource and critical for projects of genetic discovery.
New targets
With this information we will be better placed to make informed decisions regarding drug development to treat both acute and chronic infections. Furthermore, knowing what pathways are essential to the TB bacteria may also provide new vaccine and drug candidates.
Creating effective vaccines
We are also investigating processes of pathogenesis to develop improved vaccines and treatments for tuberculosis. In particular, we are searching for and identifying potential proteins of Mycobacterium tuberculosis (MTB) that could be candidates for new vaccines.
This project aims to understand how the host responds to infection with MTB bacteria - one of the most resilient chronic bacterial infection of humans - so we can make more effective vaccines.
We are also exploring how the bacterium responds to infection in the host by changing the genes it expresses after it invades host cells, and the function of selected proteins from M. tuberculosis and M. leprae, which causes leprosy).
New ways to deliver vaccines
With these newly identified candidate vaccines we are also investigating novel ways to deliver them to make them more effective and less painful to give to a person. Very few people like needles, especially young children who are often the ones who receive vaccines. Finding a relatively pain-free, easy way that delivers a more effective vaccine could be advance the global efforts in controlling TB.
Developing better treatments
With increased knowledge we are also better placed to make informed decisions regarding drug development to treat both acute and chronic infections. With the view to, ultimately, shorten the duration of treatment to just weeks instead of months.
New drug to block a TB lifeline
One of our current projects involves the screening of a new drug candidate against an essential protein or enzyme for the survival of TB bacteria. The enzyme, which had been identified by Professor Warwick Britton, is known as "Culp6". Centenary's Dr Nick West and his team worked with Dr Richard Payne from the University of Sydney's School of Chemistry to develop a new anti-TB drug to inhibit Culp6 and block the survival path of the TB bacteria.
The new drug has shown promising results at the cellular testing and it has now moved into the next stage of pre-clinical testing.
Teaching an old drug new tricks
Dr Nick West along with Dr Jamie Triccas from the University of Sydney will work with leading experts from the National University of Singapore (NUS) to investigate resistance to ethionamide, which is a drug used to treat tuberculosis when others have failed.
Using the extensive 15,000-strong library of MTB mutants, Dr West and Dr Triccas will team up with Dr Sylvie Alonso from NUS to screen the thousands of strains to identify which of these are resistant to ethionamide.
This collaboration with the NUS could uncover vital information about how drug resistance occurs against this important drug. If we can learn how the bacteria tolerates this drug, we may be able to find a way to overcome this resistance and make the drug effective again.
Using the immune system to fight TB
Our own immune response to TB disease causes damage by creating inflammation in the lungs. Understanding how this process is regulated is essential for the development of new therapies to treat the infection and control inflammation. Our group is examining the factors that control protective immunity to TB and genetic aspects that influence this response.
Understanding TB talk
We are also working to understand the chemical messengers (called cytokines) that are important in controlling inflammation. We are determining the pattern of cytokine expression and how this controls subsequent inflammation. We hope that by expressing defined cytokines that we can increase resistance to TB infection.
At the cellular level, we are investigating the inflammatory response generated following TB infection and the requirements for protective granuloma formation and maintenance.
Unleashing the might of the macrophage
The macrophage is a central cell in control of TB infection. Macrophages are the immune cells in which the MTB bacteria reside. Ironically, they are also the cells responsible for killing the invading MTB and other infections. This means TB cunningly hides itself in the very cell that is meant to seek it out and destroy it.
To overcome this dilemma, Dr Bernadette Saunders and her team are examining the factors that control macrophage activation leading to killing or containment of the mycobacteria bacilli. In particular we have examined the role of two macrophage effector molecules IDO and LRG-47 in control of mycobacterial infection. An honours student working in the laboratory, Gaya Nagalingam, demonstrated that macrophages infected with mycobacteria produce large amounts of LRG-47. Studies are underway to determine if over expression of this molecule influences development and maintenance of protective immunity to TB infection. It is hoped that this research may lead to the discovery of alternative therapies to treat tuberculosis infection.
Uncovering risky or resistant genes
We are working to uncover new genes that regulate resistance or susceptibility to TB infection and determine how these genes regulate these processes.
At a genetic level, we are determining the genetic influences that control susceptibility to TB. Over the past five years we have been investigating polymorphisms in the P2X7 gene and have identified a single nucleotide polymorphism in the P2X7R gene that confers increased susceptibility to extra-pulmonary tuberculosis. Studies examining other SNPs in the P2X7 gene and TLR1 and 2 are ongoing.
In 2007, with collaborators Professor Chris Goodnow at the Australian Phenomics Facility Australian National University, Professor Richard Cornell at the Wellcome Trust in Oxford, UK and Dr Mark Lathrop in France, we were awarded a large five year grant by the Wellcome Trust to identify new genes that influence resistance and susceptibility to TB. It is hoped that this exciting new project will uncover new factors that regulate resistance and susceptibility to TB.
Improving TB control
We are also undertaking studies in Vietnam into the prevalence of active tuberculosis among people in households of people with tuberculosis. Family members of people with active TB are at higher risk of contracting the infection so there is a strong case for developing a screening program in this key group.
Funding from the Bushell Foundation allowed the Centenary Institute and Woolcock Institute to collaborate with the National Lung Hospital in Vietnam to roll out a pilot study in four districts in Hanoi. The initial results are promising with family members recording double the rate of disease than the national average in Vietnam.
The pilot study has enabled the Centenary Institute's Professor Warwick Britton and the Woolcock Institute's Professor Guy Marks to win funding for a second much larger study, which is a randomised controlled trial of active screening of household contacts across 71 District Clinics throughout 8 Provinces in the north, centre and south of Vietnam.
This study represents a major new direction in tuberculosis control in Vietnam, with an important role in informing future public health policy in Vietnam and possibly other countries with high rates of TB.
Read a Vietnam Field Report from Dr Greg Fox - our PhD researcher based in Vietnam.
Please join Centenary Institute and contribute to our research to overcome TB. Visit www.tb.org.au or click the button on the left to donate.
