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Epigenetic Control Of Antigenic Variation In Plasmodium Falciparum
Funder
National Health and Medical Research Council
Funding Amount
$505,563.00
Summary
Malaria is an enormous global health problem that kills millions of people each year. Humans develop only partial immunity to malaria only if they survive many years of repeated infection. Much of the difficulty in developing immunity to malaria lies in the ability of the causative agent, Plasmodium falciparum, to continually change the properties of its surface coat. The parasite achieves this immune evasion through a process called antigenic variation. Genetically identical parasites can expre ....Malaria is an enormous global health problem that kills millions of people each year. Humans develop only partial immunity to malaria only if they survive many years of repeated infection. Much of the difficulty in developing immunity to malaria lies in the ability of the causative agent, Plasmodium falciparum, to continually change the properties of its surface coat. The parasite achieves this immune evasion through a process called antigenic variation. Genetically identical parasites can express different surface coats, and the control of this process is superimposed above the level of genetic control. This system is referred to as epigenetic control. Epigenetic control includes regulatory mechanisms such as the way that genes are packed inside the parasite, and chemical modifications to the proteins (called histones) around which genes are wrapped. We wish to understand the epigenetic control system that the parasite uses to orchestrate the phenomenon of antigenic variation. We will use two methods to gain this understanding; the first is a genetic screen that will create mutations in the parasite using jumping DNA (called transposons) that will break down the control mechanism behind antigenic variation. Identifying the mutated genes will show us which genes organize antigenic variation in normal parasites. Our second approach is to genetically knockout parasite genes that are related to the genes that govern epigenetic mechanisms in other, better understood organisms like humans and yeast. We will test the effect of these targeted gene deletions to discover which of these genes are involved in regulating antigenic variation. The insights gained from these discoveries will improve our understanding of how the malaria parasite evades our immune system. A better understanding of this immune evasion may help us to understand how to build better vaccines against malaria.Read moreRead less
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