Malaria
Hiding out in the Placenta. Investigating how glycosaminoglycans can modulate the immune system during malaria and pregnancy - also offered as MBiomedSc
Supervisors: Dr Louise Randall and Professor Stephen Rogerson
Project Site: Department of Medicine, University of Melbourne. The laboratory is located at the Peter Doherty Institute for Infection and Immunity
Contact: Dr Louise Randall E: louise.randall@unimelb.edu.au T: 8344 2181
Project description: Malaria during pregnancy can impact both the mother and the developing fetus, resulting in increased morbidity and mortality. Placental malaria is characterised by the accumulation of P. falciparum-infected red blood cells in the placenta. Parasite-derived proteins on the infected red blood cell membrane bind to chondroitin sulfate A, a glycosaminoglycan associated with the syncytiotrophoblasts and the intervillous spaces of the placenta. Studies performed in our laboratory suggest that this glycosaminoglycan can modulate the immune system response to the malaria parasite. This new project aims to examine this modulation more closely and to understand the interaction between the parasite, the placenta and the mother’s immune system.
Techniques involved: enzyme-linked immunosorbent assay (ELISA), cell culture, measurement of cytokines, real-time PCR.
Development of an ultra sensitive non-invasive point of care immunosensor for malaria elimination - also offered as MBiomedSc
Supervisors: Prof. Stephen Rogerson, Prof. Patrick Kwan, Prof. Stan Skafidas
Projects site: Doherty Institute, Department of Medicine (RMH), Centre for Neural Engineering
Contact: Professor Stephen Rogerson, E: sroger@unimelb.edu.au; Patrick Kwan, E: patrick.kwan@unimelb.edu.au
Project description: Detection of very low-density malaria infection is essential for malaria elimination, but current diagnostics are insensitive and/or costly. Supported by the Bill & Melinda Gates Foundation, this project aims to develop a low-cost, point-of-care diagnostic device based on our novel electrical immunosensor platform with ultra-sensitive detection capacity. The platform will be applicable to blood (for detection of very low density infection) and saliva (for non-invasive testing) to fulfill diagnostic gaps required for malaria elimination. Our pilot data suggest superior sensitivity that can detect protein at levels three logs lower than conventional malaria rapid diagnostic tests (RDTs), and two logs lower than next generation IDTs (Infection Detection Tests).
Investigating the effects of GM-CSF and M-CSF derived human macrophages on phagocytosing P.falciparum infected erythrocytes and cytokine production - also offered as MBiomedSc
Supervisors: Dr. Adrian Achuthan and Professor Stephen Rogerson
Project site: Department of Medicine (RMH), University of Melbourne
Contact: Dr. Adrian Achuthan T: 8344-3298 E: aaa@unimelb.edu.au;
Project Description: An important way in which the body clears malaria infection is through opsonisation of P. falciparum-infected erythrocytes (IE) and phagocytosis by monocytes/macrophages. This process leads to activation of signalling pathway and cytokine production. Current studies utilize human monocytes cultured in vitro in the presence of either granulocyte-macrophage colony stimulating factor (GM-CSF) or M-CSF to produce monocyte-derived macrophages (MDMs). Classical activation of monocytes by GM-CSF yields “M1-like” MDMs with a pro-inflammatory cytokine profile while M-CSF promotes “M2-like” MDMs that produce an anti-inflammatory cytokine repertoire. In this project you will explore the effects of IE phagocytosis by M1-like and M2-like MDMs on cytokine production and trafficking. Furthermore, you will be investigating the expression and function of signalling proteins that govern phagocytosis and cytokine secretion in these two types of MDMs.
Techniques: The project involves a range of molecular and cell biology techniques including culture and purification of P. falciparum-infected erythrocytes, isolation and culture of human monocytes/macrophages , qPCR to assess cytokine mRNA, ELISA to measure cytokine secretion and Western blotting and confocal imaging to determine protein expression and localisation.
A role for Adipose Tissue in Malaria? - also offered as MBiomedSc
Supervisors: Dr Elizabeth Aitken & Professor Stephen Rogerson
Project Site: Department of Medicine (RMH), Peter Doherty Institute
Contact: Dr Elizabeth Aitken T: 03 8344 1972 E: Elizabeth.aitken@unimelb.edu.au and Professor Stephen Rogerson T: 03 8344 3259 E: sroger@unimelb.edu.au
Project description: The pathology associated with malaria is partly caused by a strong inflammatory immune response to the Plasmodium parasite. Adipose (fat) tissue has recently been shown not to be an inert energy store, but a tissue which actively regulates the immune response. Interestingly, we know that the parasite likes to sequester in the adipose tissue but we don`t know much else. With increasing obesity worldwide, this could be important for development of severe malaria. In this project you will study adipose tissue from people and mice infected with Plasmodium parasites. You will discover where in the adipose tissue the parasites are, if (and which) immune cells are also there and if there are any other changes in adipose tissue associated with infection. Techniques will include: Immunohistochemistry, light microscopy, image analysis software.
Investigating the acquisition and maintenance of immunity to malaria in infants and pregnant women
Supervisor: Dr Freya Fowkes, Head, Malaria Epidemiology Group, Centre for Population Health, Burnet Institute
Project Site: Burnet Institute
Email: E: Fowkes@burnet.edu.au
Project Description: Immunity to infectious diseases during pregnancy remains an intriguing area with immunologic and physiologic changes during pregnancy rendering pregnant women to be more susceptible to, and more severely affected by, infectious diseases. Malaria is one of the most important pathogens in pregnancy and world-wide it is estimated that 50 million women living in malaria endemic areas become pregnant. Despite acquiring substantial pre-existing blood-stage immunity pregnant women typically develop higher parasite densities compared to non-pregnant adults, placental infection and associated complications. Very little is known about antibody acquisition, maintenance and boosting during or after gestation. Furthermore little is known about maternal transfer of antibodies and subsequent maternal antibody decay and infant antibody acquisition in infants born in malaria endemic areas.
We have samples from several established longitudinal cohorts of pregnant women and infants that can address questions of antibody acquisition and maintenance through antibody assays and epidemiological analyses. Findings will help us understand how immunity develops and is maintained against infectious diseases.
Understanding the targets and mechanisms of human immunity to malaria
Supervisor: Professor James Beeson, Dr Jack Richards
Project site: Burnet Institute
Email: E: beeson@burnet.edu.au jack.richards@burnet.edu.au
Project Description: This project will focus on identifying the key antigens that are targets of protective immunity against malaria and understanding the mechanisms mediating immunity, which includes antibodies and cell-mediated responses. This knowledge is crucial for the development of effective vaccines against malaria. The project may combine detailed studies of immune responses with clinical and population studies in Africa, Asia, and Papua New Guinea. It will examine how immune responses protect children from malaria, or protect pregnant women and their developing babies from the devastating consequences of malaria in pregnancy. The studies would particularly focus on understanding antibody acquisition, maintenance and boosting and how antibodies neutralize and clear malaria parasites in the blood, and examine interactions with monocytes/macrophages and dendritic cells, and understanding the nature and specificity of antibody responses.
For all queries please contact Arzum, arzum.cubuk@burnet.edu.au
Vaccines against malaria
Supervisor: Professor James Beeson, Dr Jack Richards
Project site: Burnet Institute
Email: E: beeson@burnet.edu.au jack.richards@burnet.edu.au
Project Description: The aim of this project is to evaluate candidate antigens as potential malaria vaccines, understand what combinations of antigens could be use to generate the most effective immune responses, and understand the protective activity of vaccine-induced immune responses. These studies will focus on several leading candidate antigens (AMA1, EBAs, PfRh, MSP2), and other promising antigens. They will use novel approaches in molecular biology, cell biology and immunology to address these aims. In addition, the project could include working on optimising vaccine approaches to induce potent protective immune responses (e.g. improving antigen presentation). The project could focus on vaccines for P. falciparum and P. vivax, which are the two main causes of human malaria.
For all queries please contact Arzum, arzum.cubuk@burnet.edu.au
Identifying targets and mechanisms of the acquired immunity to severe malaria in children
Supervisors: Professor James Beeson, Dr Jack Richards, Professor Stephen Rogerson
Project Site: Burnet Institute
Contact: Professor James Beeson E: beeson@burnet.edu.au jack.richards@burnet.edu.au; sroger@unimelb.edu.au
Project description: Malaria caused by Plasmodium falciparum is a leading cause of mortality and morbidity globally, particularly among young children. After repeated exposure, individuals develop effective immunity that controls blood-stage parasitaemia, thereby reducing clinical symptoms and life-threatening complications. Antibodies are important mediators of this acquired immunity. The demonstration that naturally acquired antibodies are associated with protection from malaria is one of the criteria used to objectively prioritize malaria antigens for malaria vaccine development.
We have recently completed a case-control study of severe malaria in children living on the North coast of Papua New Guinea. Cases were identified at Madang hospital and were defined as having severe malaria according to the World Health Organization criteria. Each case of severe malaria was matched to a healthy community control. Blood samples were taken from cases at the time of hospital admission and when the patient had recovered. For controls, samples were taken at the time of enrolment into the study. We would like to determine levels of antibodies to a range of malaria antigens by Enzyme-linked immunosorbent assay (ELISA), flow cytometry and functional antibody assays. The levels of these antibodies will then be related to clinical outcome using statistical analysis including regression techniques.
These findings will help us understand how immunity contributes to protection from severe malarial disease progression. The findings are valuable for advancing vaccine development by providing evidence supporting certain malaria antigens as targets of protective immunity.
For all queries please contact Arzum, arzum.cubuk@burnet.edu.au
Healthy Mothers, Healthy Babies in Papua New Guinea - The Impact of Nutrition, Malaria and STIs on pregnant women and infants
Supervisors: Professor James Beeson, Dr Freya Fowkes, Dr Philippe Boeuf
Project Site: Burnet Institute
Contact: beeson@burnet.edu.au freya.fowkes@burnet.edu.au; Philippe.boeuf@burnet.edu.au
Project description: In many resource-poor regions globally, pregnant women experience high rates of malaria, under-nutrition and sexually transmitted infections (STIs) which can lead to maternal morbidity and mortality and in infants, low birth weight (LBW) resulting in a significant number of infant deaths each year. In these settings, LBW is due to fetal growth restriction and preterm delivery. However the link between nutrition, malaria and STIs and these birth outcomes have yet to be elucidated.
At the Burnet Institute, we have initiated a unique research program in rural PNG, called Health Mothers Health Babies, in partnership with the PNG Institute of Medical Research, East New Britain Provincial Goverment, University of PNG, the National Department of Health, and others. We have undertaken a longitudinal study of 700 pregnant women attending antenatal care, and followed them through to delivery. Among these women we will measure markers of nutrition and evaluate micronutrient deficiencies, determine malaria and STIs. The association of nutrition, malaria, and STIs during pregnancy with respect to birth outcomes will then be assessed using epidemiological techniques. The objective of this project is to determine the major preventable causes of poor maternal health and LBW to enable the development of future interventions to improve health and pregnancy outcomes. This project is offered as a laboratory or epidemiological project, or a combination of the two depending on student interests.
For all queries please contact Arzum, arzum.cubuk@burnet.edu.au
Development of novel point of care diagnostics tests and surveillance tools
Supervisors: Professor James Beeson, Dr Philippe Boeuf, Associate Professor David Anderson
Project Site: Burnet Institute
Contact: beeson@burnet.edu.au Philippe.Boeuf@burnet.edu.au anderson@burnet.edu.au
Project description: There is an urgent need for diagnostic and surveillance tests that could be used in resource-poor settings. These include vaccine antibody testing (malaria, measles, HBV, pneumonia and others) to assess vaccine coverage in populations, and sero-surveillance tools for monitoring and tracking major infectious diseases. The limited resources and health care infrastructure in many disease-endemic countries means that tools for evaluating the vaccine status of patients, vaccine coverage in populations and for disease surveillance need to be simple to perform without a requirement for laboratory facilities or advanced equipment. The tests need to be being semi-quantitative, have a long shelf-life, stable for periods at ambient temperature, and easy to perform and interpret to ensure their suitability to the specific conditions to resource-poor settings. This project will work towards the development of novel semi-quantitative point-of-care rapid tests and investigate different approaches to improve sensitivity and quantitation. This will build on Burnet's extensive expertise in diagnostic test development and strong links to communities that experience a high burden of disease and have an urgent need for new point-of-care tests. The development of new low cost point-of-care tests for major diseases would facilitate major advances in disease control in resource-limited settings.
For all queries please contact Arzum, arzum.cubuk@burnet.edu.au
Developing new assays to identify mechanisms of human immunity to malaria
Supervisor: Dr Philippe Boeuf, Professor James Beeson, Dr Jack Richards
Project site: Burnet Institute
Contact: E: philippe.boeuf@burnet.edu.au; james.beeson@burnet.edu.au ; jack.richards@burnet.edu.au
Project Description: Malaria caused by Plasmodium falciparum is a leading cause of mortality and morbidity globally, particularly among young children. After repeated exposure, individuals develop effective immunity that controls blood-stage parasitaemia, thereby reducing clinical symptoms and life-threatening complications. Antibodies are important mediators of this acquired immunity. The demonstration that naturally-acquired antibodies are associated with protection from malaria is one of the criteria used to objectively prioritize malaria antigens for malaria vaccine development.
This project will focus on developing new assays to identify the antibody-dependent mechanisms that mediate protective immunity against malaria. This knowledge is crucial for the development of effective vaccines against malaria. The project may combine detailed studies of immune responses with clinical and population studies in Africa, Asia, and Papua New Guinea. It will examine how immune responses protect individuals from malaria; especially how antibodies interact with immune cells to neutralize and clear malaria parasites in the blood.
(For all queries, please contact Arzum, arzum.cubuk@burnet.edu.au)
Screening for anti-malarial drugs that block trafficking in parasites
Supervisors: Dr Paul Gilson, Dr Ben Dickerman, Dr Freya Fowkes
Project Site: Burnet Institute, 85 Commercial Rd, Melbourne
Contact: E: paul.gilson@burnet.edu.au
Project description: Malaria is a devastating parasitic disease that infects hundreds of millions of people each year, tragically killing about half a million, mainly children. Anti-malarial drugs are the main weapons used to combat infection but alarmingly parasites are starting to become resistant to the latest frontline drugs. For this reason new drug targets need to be identified and new medicines developed to for future use. One potential suite of targets are the protein trafficking pathways used by parasites to shuttle proteins around not only their own cells but also those of the human host cells they infect. This project will involve screening libraries of parasite killing drugs to identify compounds that block protein trafficking. Parasites treated with the trafficking drugs will then be studied to determine where the drugs block trafficking and what their potential enzyme targets might be. This work could form the basis for the future development of novel anti-malarial chemotherapies.
Techniques involved: Cell culture, luciferase based growth assays, live cell microscopy of parasites.
Host cell modificatins in malaria parasites - also offered as MBiomedSc
Supervisors: Dr Paul Gilson, Dr Hayley Bullen, Dr Sarah Charnaud, Dr Freya Fowkes
Project Site: Burnet Institute, 85 Commercial Rd, Melbourne
Contact: E: paul.gilson@burnet.edu.au
Project description: Malaria parasites extensively modify the red blood cells they infect to enable them to grow rapidly and to avoid host immunity. To modify their host cells, the parasites make and then export hundreds of proteins into the host compartment. These proteins traffic to different regions within the host and form a number of complexes and structures that contribute to parasite virulence. We have made a number of key discoveries regarding the methods used by parasites traffic their virulence proteins and this project hopes to extend this work further to assess the value of the trafficking systems as future targets for anti-malarial drugs.
Techniques involved: Cell culture, luciferase based growth assays, live cell microscopy of parasites.