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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
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
Towards Novel Therapies For Scabies: Functional Analysis Of Sarcoptes Scabiei Aspartic Proteases.
Funder
National Health and Medical Research Council
Funding Amount
$328,231.00
Summary
Scabies is a significant problem in disadvantaged populations worldwide, particularly Australian Aboriginal communities where up to 65% of people can be affected. Our research will investigate the role that aspartic proteases play in the interaction of the mite with its host. We will examine methods of interfering with the function of these proteins with the aim of designing new, effective treatments for scabies.
The Impact Of Interplays Between Viral Immune Evasion Proteins And Host Cell-surface Receptors On Viral Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$482,710.00
Summary
Herpesviruses can cause infections that persist for the lifetime of the individual. These viruses have evolved a range of mechanisms to evade the host's immune response that would otherwise eliminate them. One member of the herpesvirus family that is replete with methods for avoiding the immune response is cytomegalovirus. This virus, while not causing symptoms in healthy people, is a significant cause of disease and mortality in indivuals who are immunosuppressed such as AIDS patients or people ....Herpesviruses can cause infections that persist for the lifetime of the individual. These viruses have evolved a range of mechanisms to evade the host's immune response that would otherwise eliminate them. One member of the herpesvirus family that is replete with methods for avoiding the immune response is cytomegalovirus. This virus, while not causing symptoms in healthy people, is a significant cause of disease and mortality in indivuals who are immunosuppressed such as AIDS patients or people undergoing transplantation, or in neonates who have poorly developed immune responses. In the current project we will explore how virally encoded proteins that bind to cell surface receptors expressed on a class of immune effector cell called the Natural Killer (NK) cell, can interfere with the functions of these cells. We will seek to define the NK cell proteins that are specifically bound by these viral proteins and also make deletion mutants of these viral genes to assess what effect knocking out these genes has on virus-caused disease. These studies will provide important insights into novel mechanisms of viral immune evasion and may provide insights into how therapies could be developed that interfere with the functions of these viral proteins.Read moreRead less
Immunobiology Of Early Pregnancy - A Model Of Virus-induced Abortion
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
The lack of 'self' molecule expression on the trophoblast cells of the placenta which interface directly with the mother's circulation, as well as the local suppression of the mother's immune response at this interface, may be important factors in the successful implantation of the embryo. This immunological 'silence' allows the embryo, whose paternal genetic contribution makes it immunologically foreign to the mother, to escape the rejection reaction normally associated with foreign graft trans ....The lack of 'self' molecule expression on the trophoblast cells of the placenta which interface directly with the mother's circulation, as well as the local suppression of the mother's immune response at this interface, may be important factors in the successful implantation of the embryo. This immunological 'silence' allows the embryo, whose paternal genetic contribution makes it immunologically foreign to the mother, to escape the rejection reaction normally associated with foreign graft transplantation. Infection with flaviviruses increases the concentrations of cell surface self and adhesion molecules in vertebrate cells, including the trophoblast cells of the placenta. As a result, these molecules can then be recognised by the maternal immune system and the embryo targeted for destruction. We hypothesise that the induction of these molecules by this and other viruses may break the immunological silence of the early embryo and reverse the local suppression of the maternal immune response. This would result in maternal immune rejection of the embryo and abortion. This initial sensitisation of the mother by the virus might be one of the reasons that some women suffer recurrent abortions. We will use a novel viral mouse model where we implant virus-infected embryos into receptive animals to enable us to dissect out the unusual requirements for induction of maternal anti-viral immunity during pregnancy. This model was developed in our laboratory to directly test our hypotheses. It does not cause systemic illness in the mother which itself can lead to non-specific abortion. This model therefore can for the first time elucidate the specific mechanisms associated with the delicate balance between eradicating virus and maintaining pregnancy. Results from this project will inform rational design of treatment of recurrent abortions in the community.Read moreRead less
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
Immunopathogenesis Of West Nile Virus Encephalitis - Requirement For Interferon-gamma-dependent Soluble Mediators
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Flaviviruses transmitted by arthropods cause considerable illness and death world-wide by their propensity to cause encephalitis. In August 1999, an outbreak of West Nile virus (WNV) encephalitis occurred in New York for the first time, indicating that these viruses are spreading beyond endemic areas. However, the mechanisms by which these viruses kill people are not at all clear. How the immune system deals with them is controlled by a complex network of interactions involving cells and soluble ....Flaviviruses transmitted by arthropods cause considerable illness and death world-wide by their propensity to cause encephalitis. In August 1999, an outbreak of West Nile virus (WNV) encephalitis occurred in New York for the first time, indicating that these viruses are spreading beyond endemic areas. However, the mechanisms by which these viruses kill people are not at all clear. How the immune system deals with them is controlled by a complex network of interactions involving cells and soluble mediators such as cytokines, chemokines, and nitric oxide, many induced or modulated by the cytokine, inteferon-gamma. Evidence suggests that these agents together influence both the types of cells that are mobilised to eradicate virus and also disease outcomes. Our hypothesis is that the host's own immune system is inadvertently responsible for encephalitis through an over-vigorous attempt to destroy the infecting virus, resulting in damage to the brain. To study WNV encephalitis, we are using a mouse model developed in this laboratory that reproduces the features of human disease. Another strain of these mice has the gene for interferon-gamma (IFN) inactivated or 'knocked out', so they cannot respond in the conventional way to virus infection. This mouse survives WNV infection significantly better than normal mice and becomes immune. Therefore we will compare cellular and soluble mediator responses of these mice during WNV infection to those of normal mice. We will also delete specific cell types making interferon-gamma in normal mice, as well as transfering such cells into knockout mice. Experiments will indicate which cell types are responsible and when particular components cause most damage. Thus, we will better understand how interferon-gamma recruits cells that mediate immune brain damage in this model. By understanding the events that lead to death in encephalitis, it may be possible to prevent or ameliorate them by means of immune intervention.Read moreRead less
The Role Of The Interaction Of The CMV M11 Immune Evasion Molecule With CD44 In Viral Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
Herpesviruses can cause infections that persist for the lifetime of the host. They have evolved many mechanisms to elude the host's immune response that would otherwise eliminate them. One memberof the herpesvirus family that is particularly adept at avoiding host immunity is cytomegalovirus. This virus, while not causing symptoms in healthy individuals, is a significant cause of disease and mortality in individuals with suppressed immune systems such as transplant and AIDS patients, and in the ....Herpesviruses can cause infections that persist for the lifetime of the host. They have evolved many mechanisms to elude the host's immune response that would otherwise eliminate them. One memberof the herpesvirus family that is particularly adept at avoiding host immunity is cytomegalovirus. This virus, while not causing symptoms in healthy individuals, is a significant cause of disease and mortality in individuals with suppressed immune systems such as transplant and AIDS patients, and in the fetus which has a poorly developed immune system. In the current project we will explore at a molecular level how a virus-encoded molecule called m11 interferes with the functions of a cellular receptor called CD44 that has a range of cell functions including cell migration, activation and proliferation and signal transduction. The interaction of m11 with CD44 modifies cell migration and is likely to affect cell activation. Defining how m11 mediates its affects will allow us to define strategies to develop potential antiviral therapies. As CD44 is also involed in contributing to a range of diseases where inappropriate inflammation develops it may be that m11, or derivatives of it, could be harnessed to ameliorate these inflammatory diseases.Read moreRead less