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Antimalarial Drugs In Pregnancy: Preclinical And Clinical Studies Of Conventional And Novel Agents
Funder
National Health and Medical Research Council
Funding Amount
$470,115.00
Summary
Women in malaria-endemic areas such as coastal PNG are at high risk of malaria in pregnancy. To prevent the substantially increased malaria-associated morbidity and mortality in mother and child, and because even asymptomatic infections can be deleterious, there has been a move to giving antimalarial drugs regularly during pregnancy regardless of the mother's clinical or parasitological status. In poor tropical countries, such treatment usually comprises safe and inexpensive agents such as chlor ....Women in malaria-endemic areas such as coastal PNG are at high risk of malaria in pregnancy. To prevent the substantially increased malaria-associated morbidity and mortality in mother and child, and because even asymptomatic infections can be deleterious, there has been a move to giving antimalarial drugs regularly during pregnancy regardless of the mother's clinical or parasitological status. In poor tropical countries, such treatment usually comprises safe and inexpensive agents such as chloroquine and Fansidar. There are two main issues with this approach. First, the efficacy of such conventional agents is waning and this increases the risk of break-through malaria. Second, there are few data on how the drugs are handled in pregnancy on which to base recommendations for treatment. We plan to collect information on the disposition and effectiveness of chloroquine and Fansidar in women with malaria in pregnancy in PNG that should allow a critical appraisal of the usefulness of current regimens in PNG and in other tropical countries where parasite resistance to these agents is emerging. Artemisinin combination therapy (ACT) in the form of a novel artemisinin drug and a longer-acting partner has been suggested as the most promising alternative therapy for malaria in pregnancy if conventional drugs fail. We plan to assess the safety of a leading ACT formulation, namely dihydroartemisinin and the chloroquine-like drug piperaquine (DHA-PQ), in animals before extending our studies to women with malaria in PNG. These latter studies will allow an evaluation of the safety and efficacy of DHA-PQ as novel therapy for malaria in pregnancy in PNG and other tropical countries.Read moreRead less
The Role Of The Innate Immune System In The Immunopathogenesis Of Malaria
Funder
National Health and Medical Research Council
Funding Amount
$82,554.00
Summary
Malaria is common worldwide, affecting 600 million people. As with many infectious diseases, it the severity of a malaria infection is not only dictated by the parasite, but also the body’s immune response to the infection. This study looks at cells that contribute to the immediate immune response in two major clinical syndromes of malaria affecting women and children: cerebral malaria and malaria of pregnancy. By understanding the immune response, we gain insights into how to limit disease.
The greatest impact of Plasmodium falciparum malaria infection in Africa is on children and pregnant women. Malaria infected red blood cells stick to receptor molecules on cells lining blood vessels. The parasite produces a family of proteins called PfEMP1, expressed on the cell surface. These PfEMP1 proteins are responsible for the sticking, and are major targets of the host immune response to malaria. We have found two particular receptor molecules, sugars called chondroitin sulphate A (CSA) a ....The greatest impact of Plasmodium falciparum malaria infection in Africa is on children and pregnant women. Malaria infected red blood cells stick to receptor molecules on cells lining blood vessels. The parasite produces a family of proteins called PfEMP1, expressed on the cell surface. These PfEMP1 proteins are responsible for the sticking, and are major targets of the host immune response to malaria. We have found two particular receptor molecules, sugars called chondroitin sulphate A (CSA) and hyaluronic acid (HA), to be particularly important in sticking in the placenta, and have identified a PfEMP1 molecule which sticks to these. We will study the role of antibodies against the parasite, and against the CSA and HA molecules, in protection against malaria. We believe that African women develop these antibodies with increasing pregnancies, protecting themselves and their babies from malaria in later pregnancies, and that men will not have these antibodies. Pregnant women who have HIV-AIDS have greater susceptiblity to malaria. We will compare antibody responses in HIV+ and HIV- women to see if this is because they produce less protective antibodies. The PfEMP1 proteins are the product of var genes. We can compare parasites using the var genes they express to fingerprint them. We will examine the var gene expression by parasites from different patients, and by the parasites circulating in the blood or stuck in the placenta (in pregnant women) or in the brain, lung, gut and other organs (of children who have died of malaria) to see if the fingerprints of var gene expression differ between these different patients, or between different places in the same patient.Read moreRead less
Placental Malaria, Placental Function, Nutrient Transport And Fetal Growth Restriction
Funder
National Health and Medical Research Council
Funding Amount
$483,517.00
Summary
Malaria infection in the placenta impairs the baby's growth, probably by causing placental inflammation. We believe this inflammation interferes with the ability of placental cells to transport nutrients such as amino acids and glucose from mother to baby. We will test this by examining the expression of genes and proteins involved in nutrient transport in placental samples from pregnant women, and in cell lines, and will examine how malaria affects growth factors that control this process.
Defining The Targets And Function Of Antibodies That Protect Against Malaria In Pregnancy
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Malaria during pregnancy is a major cause of maternal and infant morbidity and mortality globally. In this project we aim to define the targets of antibodies that protect against malaria in pregnancy and understand the importance of antibody function, determine the extent of antigenic diversity, and identify epitopes of protective antibodies. Results will provide critical knowledge on the development of immunity to malaria in pregnancy that will guide vaccine development.
Malaria In Pregnancy: Exposure, Immunity And Complications
Funder
National Health and Medical Research Council
Funding Amount
$549,723.00
Summary
Increasing malaria control efforts may lead to lack of exposure needed to develop immunity. We will use plasma samples from Africa, PNG and Asia, and measures of immunity we have developed, to discover (1) which are the most important protective immune responses and (2) how are these affected by changing exposure or new drugs. Overall, we hope to identify markers of protective immunity that can be used to identify women at most risk of malaria in pregnancy and its complications
Identifying The Targets Of Protective Immunity To Malaria In Pregnancy
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Malaria in pregnancy is a major cause of disease across many countries. Pregnant women have a high risk of malaria, and large numbers of malaria parasites accumulate in the placenta, which may lead to infant or maternal death. Malaria parasites infect the placenta by producing proteins that enable them to stick to the placenta. These malaria strains causing placental infection generally do not cause disease in non-pregnant individuals. Antibodies to the parasite proteins are produced in response ....Malaria in pregnancy is a major cause of disease across many countries. Pregnant women have a high risk of malaria, and large numbers of malaria parasites accumulate in the placenta, which may lead to infant or maternal death. Malaria parasites infect the placenta by producing proteins that enable them to stick to the placenta. These malaria strains causing placental infection generally do not cause disease in non-pregnant individuals. Antibodies to the parasite proteins are produced in response to placental infection, which may help control the infection and protect against further malaria in pregnancy. However, placental malaria parasites are able to vary the proteins they produce to avoid immune responses. In this project, we will study the parasite strains that cause malaria in pregnancy and the development of antibodies that protect pregnant women against malaria and its complications. We aim to identify the genes and proteins that parasites use to stick to the placenta, and determine how much variation occurs in these proteins. We will also specifically examine the role of one particular candidate gene called var2csa, and its protein, as this has been recently been associated with pregnancy malaria. We will examine how antibodies develop that recognise different proteins and different forms of malaria parasites, and determine the type of antibodies that protect pregnant women taking part in a longitudinal study of malaria in pregnancy in Malawi, Africa. We will also examine how antimalarial drugs taken in pregnancy influence the development of protective antibodies. Through these studies we aim to understand how the immune system combats malaria in pregnancy. This will be important for developing new methods for preventing or treating malaria in pregnancy, and improving child and maternal health.Read moreRead less
Trafficking And Expression Of PfEMP1 On The Surface Of P.falciparum-infected Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$558,189.00
Summary
Malaria causes over 2 million deaths each year. The parasite infects human red blood cells and expresses a virulence protein on the erythrocyte surface allowing it to adhere to the microcapillaries preventing clearance through the spleen. We aim to understand how the parasite is able to express this virulence protein on the parasite-infected red blood cell surface. Identification of the proteins involved will provide potential drug targets to develop novel antimalarial compounds and strategies.