Molecular Immunopathology Unit - Honours projects available in 2009
An Honours project undertaken in this lab would be administered by the Discipline of Pathology.
Focuses on understanding how malaria causes illness and death, and working out strategies to prevent this. Bacterial meningitis. Mechanisms of inflammation. The kynurenine pathway of tryptophan metabolism. Our group use mouse models of disease, tissue culture, flow cytometry, gene expression analysis, transfection, immunohistochemistry, Nuclear Magnetic Resonance and biochemical approaches in our research.
- Recent interesting publications
- Hunt NH, Grau GE. Cytokines: Accelerators and brakes in the pathogenesis of cerebral malaria. Trends in Immunology 2003;24:491-499.
- Ball HJ, Sanchez-Perez A, Weiser S, Austin CJ, Astelbauer F, Miu J, McQuillan JA, Stocker R, Jermiin LS, Hunt NH. Characterization of an indoleamine 2,3-like protein in humans and mice. Gene 2007:396:203-213.
- Miu J, Mitchell AJ, Muller M, Carter SL, Ball HJ, Saunders B, Lu B, Campbell IL, Hunt NH. Chemokine expression during fatal murine cerebral malaria and protection associated with CXCR3 deficiency. Journal of Immunology 2008:180:1217-1230.
- Understanding a key new enzyme in the kynurenine pathway
Supervisor + contact details:
- Dr Helen Ball
- Professor Nicholas Hunt
Tryptophan is an essential amino acid. Indoleamine dioxygenase (IDO) catalyses the conversion of tryptophan to kynurenine, which is then transformed into several biologically active molecules. This pathway is involved in several very important physiological and pathophysiological processes, including immunomodulation and central nervous system disorders. We recently discovered a second enzyme (IDO2) that facilitates the same reaction as IDO (now termed IDO1), but which is found in different anatomical locations.
This project will further investigate the expression pattern of IDO2 by looking at subcellular localisation and expression during development and disease states. The biochemical properties of IDO2 will be examined by determining whether IDO2 enzymatic activity in intact cells is inhibited by nitric oxide, an important mechanism for regulation of IDO1 activity. This project also may include investigating the phenotypical characteristics of an IDO2 gene knockout mouse, e.g. susceptibility to infectious disease (malaria and meningitis).
Laboratory techniques involved in this project include immunohistochemistry, immunofluorescence, quantitative RT-PCR, cell culture, transfection, biochemical assays, mouse models of disease.
- What causes death and disability in bacterial meningitis?
Supervisor + contact details:
- Professor Nicholas Hunt
- Dr Helen Ball
Bacterial meningitis kills over 150,000 people every year and many more suffer neurological consequences that persist after the infection is eliminated. We have extensive experience in uncovering the immunopathological mechanisms in cerebral malaria. We have recently established a mouse model of bacterial meningitis and our preliminary results suggest that the cytokine interferon gamma (IFNγ) plays an important role in determining whether mice with bacterial meningitis succumb to the disease. IFNγ is a key regulator of indoleamine dioxygenase-1 (IDO1) expression and thus activity of the kynurenine pathway. Activation of this pathway is observed in a number of central nervous system disorders, including cerebral malaria.
This project will further investigate the role of IFNγ in bacterial meningitis. Gene expression during bacterial meningitis in IFNγ gene knockout and wildtype mice will be compared using gene arrays to identify pathways regulated by IFNγ in bacterial meningitis. IDO1 expression is upregulated in bacterial meningitis in wildtype mice and IDO1 expression will also be investigated in the IFNγ gene knockout mice. The levels of kynurenine pathway metabolites during bacterial meningitis will be measured in both mouse strains. The neurological sequelae in IFNγ gene knockout mice that recover from bacterial meningitis will be measured in behavioural studies that compare these mice with both uninfected and antibiotic-treated mice. The progression and outcome of bacterial meningitis in IDO1 gene knockout mice will also be investigated.
Laboratory techniques involved in the project include mouse models of disease, mouse behavioural studies, quantitative RT-PCR and gene arrays, histopathological analysis, biochemical assays.
- What controls tryptophan metabolism in endothelial cells? And how does this affect control of blood pressure?
Supervisor + contact details:
- Professor Nicholas Hunt
- Professor Roland Stocker
- Dr Helen Ball
Indoleamine dioxygenases (IDOs) control the conversion of the essential amino acid tryptophan into kynurenine and other biologically important molecules. Recently we showed that expression of IDO-1 in endothelial cells (the cells that line blood vessels) is switched on by the cytokine interferon-gamma (IFNγ) during malaria infections. This also may occur in other infectious and inflammatory diseases. Production of kynurenine in this location can relax vascular smooth muscle and reduce blood pressure, to a life-threatening degree (hypotension) in some disease states.
The project will investigate the regulation of expression of the IDO-1 gene and the activity of IDO-1 protein in human and mouse endothelial cells. We will find out why kynurenine cannot be further metabolised within endothelial cells. Recently our laboratory has discovered a new enzyme, IDO-2. We will investigate whether the expression of IDO-2 can be induced in endothelial cells by various cytokines and products of pathogens. These studies will be important in establishing whether we can prevent the development of hypotension in some infectious diseases.
Laboratory techniques involved in the project include cell culture, quantitative RTPCR for IDO expression, biochemical assays of IDO activity.
