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
Exported Malaria Kinases And Red Blood Cell Remodeling
Funder
National Health and Medical Research Council
Funding Amount
$408,710.00
Summary
Malaria is a serious disease affecting half the world's population and every year, more than a million people (mostly children) die as a result of the infection. Our work will help us to understand how malaria parasites alter human red blood cells and make them stick in organs such as the brain. Preventing infected red cells from becoming stiff and sticky by developing new drugs will open up new lines of attack to combat this devastating disease.
The Mechanism Of Action Of New 5-nitroimidazole Drugs Which Are Effective Against Metronidazole-resistant Giardia
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
We have discovered new 5-nitroimidazole drugs which can overcome giardial resistance to metronidazole, the most prescribed 5-nitroimidazole drug to treat giardiasis. We will focus on defining mechanisms of action of these new 5-nitroimidazole drugs in the anaerobic gut protozoan parasite Giardia. Using biochemical techniques, we will determine whether our potent new drugs are activated more efficiently by the same mechanisms as metronidazole or by novel enzyme pathways in the parasite.
Evolution And Targeting Of Polysaccharide Biosynthesis In Leishmania Parasites
Funder
National Health and Medical Research Council
Funding Amount
$449,484.00
Summary
Leishmania are parasitic protozoa that cause devastating diseases in humans. This proposal will identify the enzymes involved in the biosynthesis of an unusual carbohydrate reserve material that accumulates in pathogenic stages of these parasites. Information on the structure and mode of action of these enzymes will be used to develop novel drugs that will be tested for anti-parasite activity.
Identification Of The Plasmodium Falciparum Translocon That Exports Parasite Proteins Into Their Erythocytic Hosts.
Funder
National Health and Medical Research Council
Funding Amount
$409,027.00
Summary
Up to 10% of the world's population will suffer from malaria in any given year and for over a million this disease will be fatal. This devastating disease is caused by the parasite Plasmodium falciparum that infects and destroys our red blood cells. Infected red cells are greatly modified by the parasites so they can feed and avoid elimination by the human immune system. We wish to investigate the red blood cell modification process and assess it as a potential target for anti-malarial drugs.
Functional Genomic Analysis Of Exported DNA J Molecules In The Malaria Parasite Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$529,698.00
Summary
Every day 3500 people die of malaria and more than 40% of the world s population is at risk. Malaria is one of the biggest scourges of mankind. This project aims to translate the available genomic data into functional insights using frontier technology to identify new intervention targets for P. falciparum infection. Developing novel targets against malaria is important from a humanitarian point of view, and also to safeguard Australia and its neighbouring regions against the social and economic ....Every day 3500 people die of malaria and more than 40% of the world s population is at risk. Malaria is one of the biggest scourges of mankind. This project aims to translate the available genomic data into functional insights using frontier technology to identify new intervention targets for P. falciparum infection. Developing novel targets against malaria is important from a humanitarian point of view, and also to safeguard Australia and its neighbouring regions against the social and economical implication of this disease. The malaria parasite seeks shelter from the host immune system by hiding in red blood cells, but at the same time it has to stay in contact with the blood environment. This is achieved by export of virulence factors onto the surface of malaria parasite-infected red blood cells, which are essential for the maintenance of malaria infection. Without these virulence factors the body's immune system can get rid of the malaria parasites by itself. For display on the surface the proteins have to pass several membranes and are transferred through the red blood cell. The whole transport and assembly process of the virulence factors into functional units is very complex and requires several helper and co-helper molecules. With the deciphering of the malarial genetic code it became obvious that the parasite displays an unusual large number of co-helper molecules, which are putatively exported into the red blood cell. We will generate transgenic parasites deficient in the expression of these exported co-helper proteins and assess their role on the pathogenesis of this debilitating infectious disease.Read moreRead less
Impact Of An Ivermectin Mass Drug Administration Program Against Endemic Scabies And Strongyloidiasis
Funder
National Health and Medical Research Council
Funding Amount
$1,289,786.00
Summary
Overseas studies suggest sustainable and long term benefits can be obtained through the use of ivermectin in mass drug administration programs to control parasitic infections. Our study will be a critical first step in establishing if such a program can be successful in a remote Indigenous community setting, where the disease burden from scabies and strongyloidiasis (threadworm infections) is very high.
Determining The Function Of Parasite Proteins At The Membrane Skeleton Of Malaria-infected Red Blood Cells
Funder
National Health and Medical Research Council
Funding Amount
$392,036.00
Summary
Malaria is a serious disease that frequently kills its victim after a bout of high fever and coma. The most vicious form of malaria is caused by a minute parasite called Plasmodium falciparum that lives inside red blood cells. As these parasites grow, they make some dramatic renovations to their red blood cell home that make it become very stiff and sticky. Instead of flowing around the body like normal red blood cells, the infected cells become trapped in small veins and can no longer carry out ....Malaria is a serious disease that frequently kills its victim after a bout of high fever and coma. The most vicious form of malaria is caused by a minute parasite called Plasmodium falciparum that lives inside red blood cells. As these parasites grow, they make some dramatic renovations to their red blood cell home that make it become very stiff and sticky. Instead of flowing around the body like normal red blood cells, the infected cells become trapped in small veins and can no longer carry out their normal job. The ability of the parasite to make red blood cells stiff and sticky is what makes this type of malaria so dangerous, particularly when red cells get stuck in the brain. We plan to look at certain proteins that malaria parasites place on the walls of red blood cells because we think this is what makes them stiff and sticky. We hope this will help with the development of and urgently required ways to cure malaria.Read moreRead less