Many microbes exist in harmony with their hosts. Microorganisms capable of causing disease are called pathogens and have specialised factors designed to interfere with the host and enable invasive infection.
The study of microbial pathogenesis is designed to use a variety of in vitro and in vivo models to identify factors necessary for invasive disease. The Marshall Centre has specialised programs in understanding the pathogenesis of Burkholderia pseudomallei with Dr Mitali Sarkar-Tyson, neisserial pathogens with Dr Charlene Kahler, and leishmania with Dr Chris Peacock.
Pathogenesis of Burkholderia psuedomallei
My group has a strong interest in neglected tropical diseases and the discovery of new medical countermeasures. We are particularly interested in understanding the molecular mechanisms by which bacteria cause disease.
Our main focus is on the Gram-negative bacterium, Burkholderia pseudomallei which causes the tropical disease melioidosis which is endemic in northern Australia and South East Asia. Melioidosis is thought to be endemic in at least 45 countries worldwide, and has a predicted global burden of approximately 165,000 cases, of which 89,000 were fatal in the past year.
Even with effective antibiotic treatment, mortality rates of melioidosis in northern Australia are approximately 20 per cent. B. pseudomallei is also intrinsically resistant to many classes of antibiotics, therefore the development of novel medical countermeasures is of high priority. We have identified several virulence factors which enable B. pseudomallei to cause disease and are currently collaborating with international partners to identify novel inhibitors.
Pathogenesis of Neisseria meningitidis
Neisseria meningitidis is an obligate human pathogen that causes transmissible life-threatening sepsis and menigitis. A closely related pathogen, Neisseria gonorrhoeae, causes sexually transmitted infections in men and women.
Until recently both organisms were sensitive to antibiotics, but recent work from our lab has shown that resistance to antibiotics is steadily increasing in N. meningitidis.
N. gonorrhoeae has become multi-drug-resistant in recent years, leading to the concern of untreatable infections. In men and women chronic and repeated infections can result in infertility. We are currently using whole genome sequencing to understand the spread of these infections in Western Australia and across Australia. This work is helping us to develop policies for diagnosis, treatment and intervention with the West Australian Department of Health and PathWest.
Minimum spanning tree of MLST clonal complexes of N. meningitidis showing the prevalence of the three fHbp variants during 2000-2004 (Panel A) and 2005-2014 (Panel B). From: S. Mowlaboccus, T.T. Perkins, H. Smith, T. Sloots, S. Tozer, L.J. Prempeh, C.Y. Tay, F. Peters, D. Speers, A.D. Keil, and C.M. Kahler. (2016) Temporal Changes in BEXSERO® Antigen Sequence Type Associated with Genetic Lineages of Neisseria meningitidis over a 15-Year Period in Western Australia. PLoS One. 2016 Jun 29;11(6):e0158315.
Each circle represents a sequence type (ST) and the size of each circle is proportional to the number of isolates described by the ST. Thick black solid lines denote connections between STs which differ at one locus; grey lines denote connections between STs which differ at two or three loci.
Broken lines denote connections between STs that differ at four or more loci. The length of a line connecting two circles is proportional to the number of loci by which the two STs differ. The grey highlight groups circles which are identical at four or more loci and represents STs belonging to one clonal complex were generated by the BioNumerics software.
The clonal complexes are indicated outside the grouped circles. The colour of a circle or a sector represents the fHbp variant. FS stands for alleles containing a frameshift. The increase in fHbp-3 was associated with the emergence of cc461, the clonal expansion of cc213 and antigenic drift within cc32.
Leishmania pathogenesis mechanisms
This study looks at the characterisation of a novel Australian Leishmania and its potential as an attenuated vaccine. This involves the sequencing and characterisation of a Leishmania species recently discovered in Australia.
We are investigating the ability of this non-human pathogenic species to stimulate a protective immune response against those types of Leishmania that cause serious human disease throughout the world.
Novel parasites of Australian wildlife
This project involves the discovery of a novel species of Babesia (Babesia macropus) that causes a severe hemolytic anaemia leading to high fatality in macropods. Australian Trypansomes that are linked to the declining populations of the endangered Woylie and have impacts on other native animals.
We are looking at the virulence mechanisms involved using whole genome shotgun sequencing and transgenic parasites for use in infection assays.