Research Overview

Infection and Immunity Division

The goal of this Division is to improve current methods for preventing and treating two important parasitic diseases: malaria and leishmaniasis. Worldwide, each year malaria infects 250 million people and kills over two million. Leishmaniasis, transmitted by sandflies, may cause mild or severe disease and has become a major problem in war-torn endemic countries and in AIDS patients. Treatment of leishmaniasis is severely hampered by high toxicity, low efficacy and increasing resistance to existing drugs. Likewise, the malaria parasite has developed tolerance to drugs that formerly killed it, so we must discover how this drug tolerance developed. We believe that an understanding of the basic mechanisms of immunology, cell biology and genetics will be central to the development of vaccines and novel chemotherapeutic treatments of these diseases. A large number of malaria antigens have been identified but currently little is known of their function or their potential as vaccine candidates. An important component of our work aims to increase our knowledge of the structure and function of these proteins.

Background

Infectious diseases are the leading cause of death world wide, and have their major impact on children in the poorest countries. Successful vaccination programmes and availability of antimicrobial agents have provided major benefits for developed countries, but much remains to be done, particularly in developing countries. Almost daily we are shocked from our complacency by the threat of newly emerging infectious diseases such as HIV, newly described incurable infections, opportunistic infections in immunocompromised individuals, and multidrug resistant bacteria that demand our attention. "It is extremely important that Australia and the Hall Institute maintain its great tradition of research in microbiology and infectious diseases," says Professor Graham Brown, Head of the Infection and Immunity Division.

Our Goals

The Division of Infection and Immunity has a two-fold objective, to obtain fundamental insights into the biology and immunology of infectious diseases, as well as developing novel ways to combat these infectious agents. Our research therefore covers investigations of the molecular basis of drug resistance, mechanisms of pathogenesis and toxin action, immune evasion by pathogens, parasite and host genetics, and the development of vaccines and drugs. The work covers a wide spectrum from basic laboratory research to field applications that involve numerous international collaborations.

Historical Note

Twenty years ago, Sir Gustav Nossal and Dr Graham Mitchell, initiated the bold plan of establishing an immunoparasitology group, with the goal of applying the latest techniques in immunology and cell biology to parasitic diseases of importance to human health. After a judicious learning period with various veterinary parasites in model systems, the focus became three major parasitic tropical diseases: malaria, leishmaniasis, and schistosomiasis.

Helping to Combat Diseases of Global Importance

Malaria and leishmaniasis are rare diseases in developed nations, so why is Australia's leading medical research institute involved in research in these two diseases? Researchers of the Institute recognise the obligation to work with the World Health Organization and other international bodies to apply the most modern biomedical tools and techniques to addressing problems of global importance. Their research efforts into these diseases involve collaborations with a number of institutions within Australia and also internationally, with organisations such as the Papua New Guinea Institute of Medical Research; the Eijkman Institute for Molecular Biology in Jakarta, Indonesia; and the Wellcome Trust Centre in Blantyre, Malawi.

Strong linkages with disease-endemic countries ensures relevance of the eventual translation of the research findings into practice in these countries.

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The Host-Parasite Relationship

Good parasites do not kill their hosts. A successful relationship between a parasite and its host is one in which the parasite maintains a healthy balance with the host's immune system that allows both the parasite and the host organism to survive and fulfil the biological imperative of reproduction. In this delicate balancing act, a constant tug of war exists between the ability of the parasite to create a safe environment for growth and development in the host, and the best efforts of the host to defend against the parasite, using the immune system and genes enhancing resistance.

Malaria is a disease that still affects millions of people in the world's tropical regions, with most deaths occurring among infants and children under the age of 5 in areas of sub-Saharan Africa. Plasmodium falciparum, the most dangerous of the four Plasmodium species that infect humans, kills many of its human hosts, but many children survive and eventually develop resistance to further attacks. Some scientists study malaria in mosquitoes, but Hall Institute scientists are concentrating on the parasite in its human host.

Leishmania major, another protozoan parasite of humans, affects millions of people in tropical and temperate regions around the world. At one end of the spectrum, leishmaniasis can cause a disfiguring ulcerative disease of the skin. At the other end of the spectrum, visceral leishmaniasis is an invasive infection with a lethal outcome.

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Drug and Vaccine Development

Throughout the twentieth century, malaria and leishmaniasis have defied all efforts to develop effective vaccines. Researchers in the Division are investigating the molecular mechanisms involved in these intricate host/parasite relationships with the aim of identifying, producing and purifying candidate vaccines or targets for antiparasitic drugs. Lessons learned from understanding the host/parasite relationship can also be of fundamental importance to other areas of molecular and cell biology.

Developing vaccines and drugs demands a deep understanding of the molecular biology of the parasite, particularly the dynamics of interactions with the host and the host's immune system. Whereas much is known about how the immune system deals with virus infections, far less is known about protective responses to parasitic infection. The complexity of the parasite in host interactions demands an enormous amount of basic research, coupled with clinical research in countries where the disease is endemic.

Malaria Program

Map of Malarial endemics

Source: World Health Organization 1997

 

Leishmaniasis Program

Leishmaniasis is caused by a microscopic parasite with a predilection for a specific host cell, the macrophage. "The macrophage", says Dr Emanuela Handman, "is a large scavenger cell that roams the body engulfing and destroying invading microbes". However, Leishmania have evolved mechanisms to subvert these host "seek-and-destroy" cells for their own purposes.

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Leishmaniasis is a spectrum of diseases whose clinical manifestations depend on a combination of host and parasite factors. Leishmania donovani tends to home to the liver and spleen, causing (usually fatal) visceral leishmaniasis. Leishmania brasiliensis, in contrast, homes to the lining of the nose and throat, causing a mutilating mucocutaneous disease, and Leishmania major homes to the skin, causing the self-limiting skin ulcers called cutaneous leishmaniasis.

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Leishmaniasis affects at least 12 million individuals each year, and about 300 million people are at risk, both in the developed and developing world. In recent years, visceral leishmaniasis has surged in epidemic proportions in new areas in the Sudan, in Pakistan and in China. It has also become a major problem in AIDS patients in Europe.

To date there is no vaccine against leishmaniasis. The drugs available are toxic and expensive, and their administration is lengthy and cumbersome. Moreover, the parasites are becoming resistant to the commonly used antimony drugs.

The major aims of Dr Handman's team, are to develop a vaccine against leishmaniasis and to identify parasite targets for the design of new and specific drugs.

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A Prototype Leishmania Vaccine is Being Developed at WEHI

Over the last decade, the group has focused on the skin disease because of strong evidence that host-protective immunity develops naturally in individuals who recover from the disease.

The new vaccine being developed at WEHI, is based on a Leishmania surface component (Parasite Surface Antigen Complex 2, or PSA-2). Since this antigen is present in all Leishmania, it provides an opportunity to protect against several forms of the disease. Foremost on the list is the disseminated form of leishmaniasis, which is often fatal, and is now a major problem in AIDS patients whose immune system is impaired. Colleagues in the United States, led by Dr Diane McMahon Pratt, have shown that this parasite coat material can vaccinate and protect against the South American form of the disease.

Dr Handman says that DNA vaccines offer a very exciting new approach. "Instead of delivering the protein component itself, we can deliver the gene itself. When injected into the skin, the small DNA loop is readily taken up by the human body and decoded into the protein". Through the CRC for Vaccine Technology, the Hall Institute and the Leishmania laboratory are at the forefront of this new area of vaccinology.

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Identification of a New Leishmania Drug Target, a Proteophosphoglycan

Dr Handman's group has discovered a mucin-like component of the parasite, made up of repetitive units which polymerise into long filaments. It exists in two forms, one present on the parasite surface and another secreted from the parasite. The biological function of this novel molecule is currently under investigation, but the scientists have already deduced from its structure that it may bind to host components. It may also subvert the environment in the host macrophage, the home of this parasite.

The bright areas show the location of the mucin in the parasite body, as detected by a specific antiserum.

The unusual and unique structure of this parasite mucin makes it a very attractive drug target. This molecule is very different from anything found in humans. Therefore inhibitors which interfere with its production should be totally innocuous for the host.

The Genetic Basis of Host Susceptibility to Disease

There are strong hints that the pathologic manifestations of leishmaniasis depend, to a large extent, on the host. Working with colleagues Simon Foote and Lynden Roberts, in the Genetics and Bioinformatics Group, the Leishmania team has been able to define two regions of mouse chromosomes which appear to determine disease severity in this animal model. Mapping the actual genes responsible for this susceptibility will pave the way for identifying human susceptibility genes and reveal potential new targets for vaccine development.