Research outline - Molecular Immunopathology Unit

Within: Bosch Institute, Discipline of Pathology

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Overview of research program

Pathogenesis of malaria
Cerebral malaria is a major life-threatening complication of infection of humans with the parasite Plasmodium falciparum. Our aim is to identify new targets for therapy that will reduce the impact of cerebral malaria: not only by reducing mortality but also the long-lasting neurological complications that are seen in many of those who survive due to anti-malarial drug treatment.

We use two model systems in our research: mice infected with P. berghei, and human cells co-cultured so as to reproduce the conditions seen in the brain micro-vessels during the cerebral malaria crisis. Areas under investigation include the involvement in pathogenesis of the kynurenine pathway of tryptophan metabolism, cytokines and chemokines. Cytokines and chemokines are messenger molecules that control the immune system.

Pulmonary oedema is another serious complication of malaria infection. Using a mouse model that we have developed, we are probing the mechanisms that lead to the accumulation of fluid in lung tissue. This build-up of fluid makes breathing more difficult and seems to increase the number of deaths from malaria, particularly when it occurs together with cerebral malaria or anaemia (loss of red blood cells). Again, we are searching for new therapeutic targets through understanding the key processes that lead to fluid accumulation in the lung.

What causes death and disability in bacterial meningitis?
Our goal is to understand the mechanisms that lead to the complications associated with infection of the brain by bacteria. In this way we aim to identify adjunctive treatments, to be given along with antibiotics, which will reduce the death rate and the incidence of neurological complications in survivors. Bacterial meningitis kills over 150,000 people every year and many more suffer neurological consequences that persist after the infection is eliminated. It is important to study the pathogenesis of this disease in order to discover new ways of reducing both the death toll and the incidence of the long-term problems in survivors.

We are applying to the problem of bacterial meningitis our extensive experience of uncovering the immunopathological mechanisms in cerebral malaria. We have established a mouse model of bacterial meningitis and our preliminary results suggest that certain cytokines play an important role in determining whether mice with bacterial meningitis succumb to the disease. These cytokines also may be important in the development of behavioural defects in survivors. The kynurenine pathway also seems to be relevant in this condition. Activation of this biochemical cascade is observed in a number of other central nervous system disorders, including cerebral malaria.

Understanding a key new enzyme in the kynurenine pathway
Tryptophan is an essential amino acid. The enzyme indoleamine dioxygenase (IDO) catalyses the conversion of tryptophan into N-formylkynurenine, 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 (IDO-2) that facilitates the same reaction as IDO (now termed IDO-1), but which is found in different anatomical locations.

We now are studying the tissue and subcellular localisation of IDO2 during development and in disease states. The characteristics of a newly-developed IDO2 gene knockout mouse, e.g. susceptibility to infectious disease (malaria and meningitis), also are under investigation.

Major funding sources

  • NHMRC Project Grant Dietary fats as drivers of obesity-related inflammation. Storlien L, Hunt N, Cook D, Caterson I. 2010-2012
  • NHMRC Project Grant #571024. Mechanisms of disease in bacterial meningitis. Hunt NH, Ball HJ, Jones CA, McGregor I. 2009-2011, $453,000.
  • ARC Discovery Grant DP0987074. Indoleamine 2,3-doxygenase-2: a newly discovered enzyme with a key role in kidney function. Hunt NH, Ball HJ. 2009-2011, $290,000.
  • NHMRC Project Grant #512469. Dysregulation of cytokine networks: a key determinant of the pathogenesis of cerebral malaria. Hunt NH, Ball HJ, Grau GE. 2008-2010, $461,625.
  • NHMRC Project Grant #464893. Relationship between cell-cell interactions and disease severity in patients with cerebral malaria. Grau GE, Cook D, Hunt NH. 2007-2009, $523,500.
  • ARC Discovery Grant DP0774425. Microparticles as effectors of microvascular alternations in brain inflammation. Grau GE, Hunt NH. 2007-2009, $263,000

Selected publications

  1. Clark IA, Cowden WB, Butcher GA, Hunt NH. Possible roles of tumour necrosis factor in the pathology of malaria. Am. J. Pathol. 1987;129:192-199.
  2. Sanni LA, Tattam B, Thomas SR, Moore D, Chaudhri G, Stocker R, Hunt NH. Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in cerebral and non-cerebral malaria. Am. J. Pathol. 1998;152:611-619.
  3. Watts AD, Hunt NH, Wanigasekara Y, Bloomfield G, Roufogalis BD, Wallach D, Chaudhri G. A casein kinase I motif present in the cytoplasmic domain of most members of the TNF ligand family is implicated in “reverse signalling.” EMBO J. 1999;18:2119-2126.
  4. Hunt NH, Grau GE. Cytokines: Accelerators and brakes in the pathogenesis of cerebral malaria. Trends in Immunology 2003;24:491-499.
  5. Rae C, McQuillan JA, Parekh SP, Bubb WA, Weiser S, Balcar VJ, Hansen AM, Ball HJ, Hunt NH. Brain gene expression, metabolism and bioenergetics: Interrelationships in murine models of cerebral and non-cerebral malaria. FASEB J. 2004;18:499-510.
  6. Hansen AM, Ball HJ, Mitchell A, Miu JM, Takikawa O, Hunt NH. Increased expression of indoleamine 2,3-dioxygenase in murine malaria infection is predominantly localized to the vascular endothelium. Int. J. Parasitol. 2004;34:1309-1319.
  7. Okada F, Kobayashi M, Tanaka H, Kobayashi T, Tazawa H, Iuchi Y, Hosokawa M, Fujii J, Dinauer MC, Hunt NH. Essential role of phagocyte-derived reactive oxygen species in the acquisition of metastatic ability of tumour cells. Am. J. Pathol. 2006;169:294-302.
  8. Ball HJ, Sanchez-Perez A, Weiser S, Austin CJD, Astelbauer F, Miu J, McQuillan J, Stocker R, Jermiin LS, Hunt NH. Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice. Gene 2007;396:203-213.
  9. 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.
  10. Togbe D, De Sousa PL, Fauconnier M, Boissay V, Fick L, Scheu S, Pfeffer K, Menard R, Grau GE, Doan B-T, Beloeil J-C, Rénia L, Hansen AM, Ball HJ, Hunt NH, Ryffel B, Quesniaux VFJ. Both functional LTβ receptor and TNF receptor 2 are required for the development of experimental cerebral malaria. PLoS ONE 2008;3:e2608.

Major collaborations

  • Prof Katja Becker, University of Giessen, Germany: structure and function of indoleamine dioxygenase-2.
  • Prof David Cook and Dr Anuwat Dinudom, University of Sydney: pulmonary oedema in malaria.
  • Prof Jacob Golenser, Hebrew University of Jerusalem, Israel: immunomodulatory drugs for malaria treatment.
  • Prof Georges Grau, University of Sydney: pathogenesis of malaria and bacterial meningitis.
  • Assoc Prof Cheryl Jones, Childrens Hospital Westmead: biochemistry and immunopathology of malaria and bacterial meningitis.
  • Prof Peter Lay, University of Sydney: biochemistry of malaria and bacterial meningitis.
  • Prof Iain McGregor, University of Sydney: bacterial meningitis.
  • Prof George Prendergast, Lankenau Institute, Philadelphia, USA: physiology and pathophysiology of indoleamine dioxygenase-2.
  • Prof Roland Stocker, University of Sydney: kynurenine pathway and vascular control.
  • Dr Hajime Yuasa, Kochi University, Japan: comparative biochemistry of indoleamine dioxygenase-2.