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Understanding Interactions Between Eosinophils And Tissue-Invasive Parasitic Helminths
Funder
National Health and Medical Research Council
Funding Amount
$227,545.00
Summary
Eosinophils are blood cells which contribute to our defences against parasitic worms. Given the right opportunity, eosinophils can cause damage to some parasites within just a few hours of contact. This is quite a feat because parasitic worms are multicellular organisms which are much larger than eosinophils and which have evolved to live in the presence of active immune responses. To do it's job properly an eosinophil probably makes use of small soluble molecules in the blood and others fixed t ....Eosinophils are blood cells which contribute to our defences against parasitic worms. Given the right opportunity, eosinophils can cause damage to some parasites within just a few hours of contact. This is quite a feat because parasitic worms are multicellular organisms which are much larger than eosinophils and which have evolved to live in the presence of active immune responses. To do it's job properly an eosinophil probably makes use of small soluble molecules in the blood and others fixed to it's own cell surface, to recognize the parasite and to promote adhesion to the target. You might like to consider these molecules as hands grabbing onto handles on the surface of the parasite. The more hands there are, the better the grip and some hands grip more strongly than others. We are investigating what these molecules are and how they work. By understanding how eosinophils operate, we may be able to devise ways in which we can make them more effective. We are also trying to understand why some species of parasite are resistant to attack by eosinophils. We think that resistant parasites secrete substances which either block the binding of eosinophils to the parasite surface, or prevent the functioning of eosinophils that do bind. It is possible that these inhibitory substances may even kill the eosinophils before they can do their job. Resistant parasites might induce eosinophils to commit suicide, a useful property for us when we no longer need these cells, but a definite drawback if they still have a job to do. Parasitic worms have evolved to avoid at least some of our defences and sometimes they do this by mimicing natural processes important for regulating immune responses. In some diseases like asthma and allergy eosinophils slip from normal controls which regulate them and then they can cause tissue damage. Inhibitors of eosinophils which are produced by parasites might form the basis of new drugs to control these cells in diseases like asthma.Read moreRead less
Viral Immune Evasion From The NK Cell Ly49H Activation Receptor
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Infection with human cytomegalovirus (HCMV) remains a significant health problem for individuals whose immune systems are immunocompromised (transplant patients and AIDS patients) or poorly developed (such as the foetus and newborn children). While drugs are available to treat HCMV infection the emergence of viral drug escape mutants means there is a medical necessity to develop new therapies and vaccines against this agent. As a basis for this it is important to develop a better understand the ....Infection with human cytomegalovirus (HCMV) remains a significant health problem for individuals whose immune systems are immunocompromised (transplant patients and AIDS patients) or poorly developed (such as the foetus and newborn children). While drugs are available to treat HCMV infection the emergence of viral drug escape mutants means there is a medical necessity to develop new therapies and vaccines against this agent. As a basis for this it is important to develop a better understand the host-virus relationship to rationally design appropriate treatments. As HCMV is species specific and does not infect experimental animals, the murine cytomegalovirus (MCMV) in mice is widely used as a model for HCMV disease. MCMV infection is controlled by both innate and adaptive arms of the host's immune response. Natural killer (NK) cells constitute an important frontline defence against MCMV and understanding how they are activated is of importance to harnessing them for anti-viral control measures. Recently we have shown that NK cells are activated via the interaction of an NK cell activation receptor (Ly49H) with a MCMV-encoded ligand (m157). However, we have also found that MCMV can rapidly mutate its m157 gene to evade effective NK cell control and that wild populations of MCMV have foms of m157 that don't bind to Ly49H. Other studies suggest that m157 can bind to inhibitory NK cell receptors, such as Ly49I, and inactivate the NK cell response. This study seeks to understand the dynamics of the m157-Ly49H and m157-Ly49I interactions. As HCMV infection is also regulated at early stages by NK cells, an understanding of how CMV can rapidly mutate its m157 gene to avoid interaction with Ly49H-expressing NK cells has important implications for understanding human disease caused by HCMV, in terms of potential viral escape from NK cell surveillance.Read moreRead less
Function And Inhibition Of Plasmepsin V In Targeting Malaria Virulence Proteins Into Human Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$407,845.00
Summary
Malaria parasites dramatically renovate infected erythrocytes to survive and evade the host immune system by delivering hundreds of exported parasite proteins into the cell. The parasite protease Plasmepsin V is essential for protein export. We aim to develop potent inhibitors of this protease in the hope of blocking its function and killing the parasite. We also aim to discover the components of the trafficking pathway after cleavage by Plasmepsin V that sorts virulence proteins to the host cel ....Malaria parasites dramatically renovate infected erythrocytes to survive and evade the host immune system by delivering hundreds of exported parasite proteins into the cell. The parasite protease Plasmepsin V is essential for protein export. We aim to develop potent inhibitors of this protease in the hope of blocking its function and killing the parasite. We also aim to discover the components of the trafficking pathway after cleavage by Plasmepsin V that sorts virulence proteins to the host cell.Read moreRead less
The Role Of Mucosal-Associated Invariant T Cells In Protective And Aberrant Immunity
Funder
National Health and Medical Research Council
Funding Amount
$620,205.00
Summary
Despite their prevalence and potential therapeutic value, MAIT cells remain the least studied of all T cells. This program seeks to do paradigm shifting research into the role of MAIT cells in protective immunity to microbes and allergies. Thereby this project will significantly advance fundamental knowledge on MAIT cell biology and could furnish novel immunotherapeutic agents with an enormous potential as alternatives to microbial and allergy treatments, areas of tremendous clinical need.
Combination Immunotherapeutic Strategies For Haematological Cancers
Funder
National Health and Medical Research Council
Funding Amount
$421,747.00
Summary
Patients with lymphoma cancers initially respond well to treatment, but later relapse with disease. The immune system can be effective at controlling cancer. A potential treatment option is to boost the natural immune response against cancer. This study investigates a novel vaccine that activates a certain immune cell, NKT cells, to fight lymphomas by delivering an NKT cell-activating molecule. Outcomes will allow assessment of combining an NKT-based vaccine with established treatments for lymph ....Patients with lymphoma cancers initially respond well to treatment, but later relapse with disease. The immune system can be effective at controlling cancer. A potential treatment option is to boost the natural immune response against cancer. This study investigates a novel vaccine that activates a certain immune cell, NKT cells, to fight lymphomas by delivering an NKT cell-activating molecule. Outcomes will allow assessment of combining an NKT-based vaccine with established treatments for lymphoma.Read moreRead less
Suppression Of Immunity By The Malaria Parasite Antigen Plasmodium Falciparum Erythrocyte Membrane Protein-1 (PfEMP-1)
Funder
National Health and Medical Research Council
Funding Amount
$96,698.00
Summary
The malaria parasite P. falciparum infects red blood cells and makes the cells put on their surface a protein called PfEMP-1. The parasite can effectively “hide” by constantly changing this protein and making it unrecognizable by the immune system. PfEMP-1 can also suppress the immune system so that it can’t respond adequately to infection. Therefore, understanding PfEMP-1 function is important. I will investigate how PfEMP-1 can do this by looking at its cross talk with the immune system.
Host-virus Interactions That Define The Outcome Of Anti-viral T Cell Responses: Relevance To Viral Persistence
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Infection with human cytomegalovirus (hCMV) is normally resolved without symptomatic evidence of infection. However, severe hCMV disease can occur in immunocompromised patients in which the manifestations of disease include chorioretinitis, interstitial pneumonia and hepatitis. In immunologically immature children, congenital infection results in cytomegalic inclusion disease (CID). CID in infants causes severe neurological sequelae resulting in mental retardation, deafness and blindness. Vaccin ....Infection with human cytomegalovirus (hCMV) is normally resolved without symptomatic evidence of infection. However, severe hCMV disease can occur in immunocompromised patients in which the manifestations of disease include chorioretinitis, interstitial pneumonia and hepatitis. In immunologically immature children, congenital infection results in cytomegalic inclusion disease (CID). CID in infants causes severe neurological sequelae resulting in mental retardation, deafness and blindness. Vaccination against hCMV induced cytomegalic inclusion disease has been designated Level I (most favourable) due to the prediction that it could save lives and prevent life-long disability. Given the essential nature of CD8 T cells in CMV control and the high prevalence of CMV in society, it will be crucial to develop a vaccine capable of eliciting an efficacious T cell response which develops lasting memory. We hypothesise that mCMV has evolved mechanisms for generating an appropriate T cell response involved in viral control and the establishment of a persistent infection. The central aim of the work in the current proposal is to investigate the cellular and viral mechanisms involved in the generation of cytomegalovirus specific T cells. The proposed studies will improve our understanding of the generation of anti-viral T cell responses and hence will be relevent to further our understanding of the role of T cells in human infection. More importantly the results will provide critical insights into the rational design of suitable antiviral drugs and vaccines.Read moreRead less
Antibiotic Resistance And Host Immune Evasion In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$644,428.00
Summary
Staphylococcus aureus is one of the most common bacteria that infects humans. This project aims to characterise the mechanisms that Staph uses to develop resistance to one of our last-line antibiotics, and will determine the effects of this resistance on the ability of the bacteria to cause human disease. The work will also investigate new treatment strategies to tackle this challenging bacteria.
Understanding The Role Of NS Segments In Evading Influenza A Virus-specific Humoral And T Cell Immunity
Funder
National Health and Medical Research Council
Funding Amount
$213,812.00
Summary
Influenza viruses developed two ways to survive against host immune response: (i) mutating in its genes to escape host immune response, which may cause a new pandemic; (ii) using its NS1 protein to impair host immune response. However, little is known on how these two processes occur and whether NS1 could influence the outcome of escape mutants. By using virological and immunological methods, this study will show how viruses use different NS1 to enhance the viral escape mechanism.
I am an immunologist studying host immune responses during malaria and visceral leishmaniasis, two important human infectious diseases. I aim to identify immune responses that promote safe and effective control of parasite growth and distinguish them from