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Home  Research  Molecular Immunology

Molecular Immunology

Michael Good Staff
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Lab Head: Professor Michael Good

Malaria Research

The global impact of malaria infection needs no emphasis. Four billion people in approximately 90 different countries are at risk of developing the disease and up to 500 million cases of malaria occur each year. This results in the deaths of 2-3 million people, mainly children under 5 years of age, but also including a significant number of pregnant women. Malarious countries suffer severe impoverishment and extremely low economic growth. A study published in 2000 by the Harvard University Center for International Development estimated that, if malaria had been eradicated 35 years ago, the annual GDP for Africa would be $US100B more than it is today - a figure which dwarfs the international aid given to Africa each year. In the year 2000 alone, the cost of treatment and lost production was $US2.5B.

Despite the availability of many intervention strategies, estimates of morbidity and mortality continue to rise. This reflects the reduced effectiveness of chemotherapy and vector control programs due to the emergence and spread of insecticide-resistant mosquito vectors and drug-resistant forms of Plasmodium falciparum. Therefore, a clear understanding of host immune responses to malaria parasites is highly desirable and critical for the effective design and implementation of new drugs and vaccines.

However, the life cycle of the malaria parasite poses a number of challenges to the immune response. Different phases of the cycle express varying antigen profiles and have different locations, thus requiring differing antigenic targets and effector mechanisms. Thus, vaccines are being developed that block sporozoite entry into the liver or kill infected liver cells (pre-erythrocytic vaccine), block the parasite's cycle in red blood cells (erythrocytic vaccine) or block transmission of the life cycle from the human host to the mosquito vector.

Life cycle of the malarial parasite Plasmodium falciparum


In the Molecular Immunology Laboratory we are most interested in the asexual blood stage of the malaria parasite, which causes clinical disease. Immunity to blood stages is thought to be mediated by antibodies that block invasion, opsonize infected erythrocytes or cell mediated responses that eliminate parasites via up-regulation of inflammatory mediators. We are particularly interested in the role that either natural or vaccine-induced CD4+ T lymphocytes play in cell-mediated immunity to malaria. We have used rodent models to understand immune responses to infection and the pathology induced by the erythrocytic stage of the parasite. Our early studies of mice immunised with two of the leading malaria vaccine candidates, MSP1-19 and AMA-1, have demonstrated that CD4+ T cells are certainly critical for induction of malaria immunity acting as effector (antibody independent) and/or helper (antibody dependent) cells.

Induction of immunity by low dose infection
Given that parasite challenge (patent infection) correlated with increased apoptosis of parasite-specific T cells, we hypothesised that a limited sub-patent infection may be able to induce effective immunity while avoiding CD4+ T cell apoptosis. We first examined this hypothesis using the rodent malaria parasite, Plasmodium chabaudi chabaudi. After three subpatent infections, mice were protected against high-dose challenge with either homologous or heterologous parasites. These studies also found that splenic lymphocytes undergo apoptosis during patent but not subpatent infections. Similarly, in human studies we have demonstrated that the development of cell-mediated immunity to Plasmodium falciparum can be induced by exposure to very low numbers of malaria parasites. Interestingly, immunity was characterised by the presence of a proliferative T-cell response, involving CD4+ and CD8+ T cells, a cytokine response, consisting of interferon gamma but not interleukin 4 or interleukin 10, induction of high concentrations of nitric oxide synthase activity, a drop in the number of peripheral natural killer T cells and absence of detectable parasite-specific antibodies. These studies suggest that mice and people can be protected against the erythrocytic stage of malaria by a strong cell-mediated immune response, suggesting an additional strategy for development of a malaria vaccine.

T-cell memory to blood stage malaria
As antigen specific T-cells are required for activation of B-cells, the generation of plasma cells and reactivation of memory B-cells, the longevity of protective B-cell immunity to malaria can also be affected by the nature of the T-cell responses. Our data suggest that CD4 T-cells undergo extensive apoptosis after blood stage infection suggesting that subsequent generation of memory cells may be impaired in infected individuals. In spite of their relevance for any vaccine approach, to date, there are only few data on the persistence of T cell responses in either human or rodent malarias. Our current interests include characterisation of the mechanisms for generation of malaria-specific T-cell memory cells and their role in immunity to re-infection.

Immunological memory of blood stage malaria
Immunological memory mediates long term protection against disease. As antigen specific T-cells are required for activation of B-cells, the generation of plasma cells and reactivation of memory B-cells, we are actively investigating various aspects of immunological memory. We have previously shown that CD4 T-cells undergo extensive apoptosis after blood stage infection suggesting that subsequent generation of memory cells may be impaired in infected individuals. In spite of their relevance for any vaccine approach, to date, there are only few data on the persistence of memory responses in either human or rodent malarias. Our current interests include characterisation of the mechanisms for generation of malaria-specific T-cell and B cell memory cells and their role in immunity to re-infection.

Deletion of parasite-specific memory B cells during infection
Our studies have also extended to characterise parasite-specific memory B-cell responses following immunisation and challenge infection. Although high titers of antibodies against one of the leading malaria vaccine candidates, MSP1-19 (C-terminal fragment of the merozoite surface protein-1) have been shown to mediate complete protection in model systems, it was not clear whether this vaccine candidate could generate long-term protection. Similar to our observations on parasite-specific- CD4 T-cells, we found that functional memory cells generated by merozoite surface protein-1, per se, do not offer any protection. This is because the parasite induces deletion of vaccine-specific memory B cells as well as long-lived plasma cells including those specific for bystander immune responses. Our study demonstrates a novel mechanism by which Plasmodium ablates immunological memory of vaccines, which would leave the host immuno-compromised. We are now characterising the mechanism of such deletion.

Changes to Dendritic cell function during malaria
The severity of malaria can range from asymptomatic to lethal infections. However, the molecular and cellular factors responsible for these differences in disease severity are poorly understood. Since Dendritic cells (DC) initiate immune responses, we have compared their phenotype and function following infection with either non-lethal or lethal species of rodent parasites to identify their contribution to disease severity. These studies suggest that changes to the DC function following malaria contribute to disease severity. We are actively investigating the mechanism by which DC mediate control of the disease.

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Staff

Labhead: Professor Michael Good
Senior Research Officers: Dr Michelle Wykes
Dr Alberto Pinzon-Charry
Dr Colleen Olive
Research Assistants: Ms Vivian Anderson
Ms Xue Qin Liu
Ms Virginia McPhun
PhD Scholars: Ms Yawalak Panpisutchai
Ms Meru Sheel
Visiting Scientists: Dr Huji Xu

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Funding

We gratefully acknowledge support from the following organisations and funding bodies:

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Last Modified: May 13 2008