Malaria is characterised by defective T cell responses, particularly suppressed T cell growth. T cells are critical to malaria protection and defective immune responses are likely to benefit the parasite. We want to find out how immune-responses are turned off in malaria, so that then we can do something about this, and help fight off the parasite. Malaria kills over 2 million children each year and there is no effective vaccine. We have two important clues as what may be happenning to cause sup ....Malaria is characterised by defective T cell responses, particularly suppressed T cell growth. T cells are critical to malaria protection and defective immune responses are likely to benefit the parasite. We want to find out how immune-responses are turned off in malaria, so that then we can do something about this, and help fight off the parasite. Malaria kills over 2 million children each year and there is no effective vaccine. We have two important clues as what may be happenning to cause suppressed T cell growth during malaria infection. Firstly, we found a massive increase in T cells expressing a surface molecule called CD38 duirng infection. Increases in these cells correlated with decreases in the ability of the T cells from the animals to grow. Indeed, other researchers had observed that in mice CD38 T cells can suppress immunity. Secondly, we hypothesized that they may be responsible for the impaired T cell reactivity observed during acute malaria, and the general poor state of immune responses in humans living in areas where they are being constantly infected by the parasite. Indeed, when we removed cells expressing CD38 from blood cells from such individuals, these 'recovered' and were able to grow much better in our assays. Therefore we propose that CD38 T cells are importnat mediators of malaria immuno-suppression. We now want to understand how the parasite induces these CD38 T cells, and how their ability to suppress T cell responses can benefit the parasite. Knowing this we aim to develop vaccines which can avoid being turned off by malaria. T cells expressing CD38 are also increased in cancer and acute viral disease, such as late stage HIV. Understanding their role in malaria will also give us new clues to fight such diseases.Read moreRead less
Modification Of Dendritic Cell Function And Priming Of Protective Immunity By Malaria Blood-stage Parasites
Funder
National Health and Medical Research Council
Funding Amount
$316,500.00
Summary
Approximately 2 billion individuals live in areas where malaria is a risk. Children and naive individuals who get infected for the first time, usually travellers, are most at risk of dying from a Plasmodium falciparum infection, with an estimated 2 million children under 3 years of age killed each year. Surviving adults living in malarial areas have partial immunity after a series of infections. It is unclear how this protective immunity, particularly cellular immunity is acquired, and also uncl ....Approximately 2 billion individuals live in areas where malaria is a risk. Children and naive individuals who get infected for the first time, usually travellers, are most at risk of dying from a Plasmodium falciparum infection, with an estimated 2 million children under 3 years of age killed each year. Surviving adults living in malarial areas have partial immunity after a series of infections. It is unclear how this protective immunity, particularly cellular immunity is acquired, and also unclear why it takes so long to develop. Recent advances in immunology have indicated that Dendritic Cells (DCs) are necesssary to induce effectively cellular immunity and prime memory responses. DCs take up foreign proteins and show them to T cells resulting in their activation. T cells are critical for the establishment of long-term protective immunity to malaria. However, it has not been known if DC can take up malaria parasites or malaria infected red-blood cells and process them to activate protective T cell responses. Our preliminary data shows that both human and mouse DC can take up parasitised red-cells, but that the interaction of parasite derived proteins on the surface of the red cell with DC receptors causes a defect in DC maturation. This defect may prevent effective priming of T cells during natural malaria infection, contributing to the poor development of immunity in malaria endemic areas. Given these novel fundamental findings, it is now important to elucidate: 1) The nature of the DC defect induced by the parasites 2) Assess whether this is a common feature of all Plasmodia, or whether it may relate to strain virulence 3) Determine the nature and extent of the malaria specific response induced by the defective DC. Understanding how parasites may be able to sabotage a critical inducing component of the immune system has wide implications for the use of any immuno-therapies in malaria endemic regions.Read moreRead less
Functional Characterisation Of A Maurer's Cleft Protein Involved In Adhesion Of Malaria-infected Red Blood Cells
Funder
National Health and Medical Research Council
Funding Amount
$160,500.00
Summary
Malaria is a serious disease that affects half of the world's population and frequently kills humans after a bout of high fever and coma. Many of those who die are young children who live in areas of the world where health care is very poor. The effectiveness of drugs that we currently have available to prevent or treat malaria is rapidly reducing and there is no vaccine available to prevent people from catching the disease. Our research is important because in order to make better medicines for ....Malaria is a serious disease that affects half of the world's population and frequently kills humans after a bout of high fever and coma. Many of those who die are young children who live in areas of the world where health care is very poor. The effectiveness of drugs that we currently have available to prevent or treat malaria is rapidly reducing and there is no vaccine available to prevent people from catching the disease. Our research is important because in order to make better medicines for malaria we have to get to know more about how the malaria parasite makes people sick. The most vicious form of malaria is caused by a tiny parasite called Plasmodium falciparum that lives inside the red blood cells in our bodies. As these minute parasites grow, they make a lot of major changes to the red blood cells and as a result they become very stiff and sticky. This is very bad for the infected person because instead of flowing around the body like normal red blood cells, the infected cells become trapped in small veins and can no longer do their normal job. The ability of the parasite to redecorate red blood cells and make them stiff and sticky is what makes this type of malaria so dangerous, particularly when red cells get stuck in the brain. The research that we will do here will help us to understand the ways in which the malaria parasite sends out these sticky substances to the walls of red blood cells. Eventually, this will help us to find ways to stop the red blood cells from becoming sticky and prevent so many people from becoming very sick and dying with malaria.Read moreRead less
Cytosolic And Organellar TRNA Synthetases In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$424,262.00
Summary
Malaria is a major worldwide infectious disease. The disease kills around 2 million people every year, and current drugs are increasingly failing due to parasite drug resistance, creating an urgent demand for new drugs, that inhibit different targets. I will study a new class of parasite drug targets, the tRNA synthetase enzymes to find novel inhibitors. Compounds blocking these enzymes may lead to new drugs to combat malaria.
Comparative Pathophysiology And Clinical Epidemiology Of Knowlesi Malaria
Funder
National Health and Medical Research Council
Funding Amount
$267,172.00
Summary
The simian parasite P. knowlesi is the most common cause of malaria in Malaysia and can cause severe and fatal disease. We are currently conducting a study of all malaria patients admitted to a tertiary referral hospital in Sabah, Malaysia. This will allow us to describe the epidemiological and clinical features of the hospitalised patients, including changes over time. We are also conducting novel pathophysiological studies which will allow us to understand how P. knowlesi causes sever disease.