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Viral Factors Involved In Flavivirus Replication And Virus-host Interactions
Funder
National Health and Medical Research Council
Funding Amount
$743,696.00
Summary
With our increased understanding of virus-host interactions it has become apparent that small, non-structural proteins and small RNAs of most viruses are vital for numerous, often multiple, functions in the viral life cycle. In the proposed project, we seek to gain a detailed understanding of the functions of small nonstructural protein NS2A and small abundant viral RNAs of medicaly important encephalitic flaviviruses, which have remained so far elusive and are at the cutting-edge in the researc ....With our increased understanding of virus-host interactions it has become apparent that small, non-structural proteins and small RNAs of most viruses are vital for numerous, often multiple, functions in the viral life cycle. In the proposed project, we seek to gain a detailed understanding of the functions of small nonstructural protein NS2A and small abundant viral RNAs of medicaly important encephalitic flaviviruses, which have remained so far elusive and are at the cutting-edge in the research field. We anticipate that with a better understanding of the roles of these factors in flaviviral replication and pathogenesis, novel targets for antiviral therapies and-or molecular determinants for inclusion in candidate vaccines will be identified.Read moreRead less
Asthma is a major health problem for the Australian community. Recent studies have shown increasing numbers of people of all ages are developing asthma. Despite extensive asthma research and the development of new asthma drugs, asthma remains a leading cause of ill- health, especially in children. In many cases the deterioration in asthma symptoms is related to a cold or flu like illness, Viruses are the leading cause of these infections and are known to make asthma symptoms worse. How they do t ....Asthma is a major health problem for the Australian community. Recent studies have shown increasing numbers of people of all ages are developing asthma. Despite extensive asthma research and the development of new asthma drugs, asthma remains a leading cause of ill- health, especially in children. In many cases the deterioration in asthma symptoms is related to a cold or flu like illness, Viruses are the leading cause of these infections and are known to make asthma symptoms worse. How they do this is not completely understood. Asthma causes a unique type of inflammation in the airways, which is present in even mild asthma and can be controlled by medication. Viruses also cause inflammation by infecting the lungs. Viruses can cause severe attacks of asthma even when asthma appears controlled on medication. The ways in which virus infections do this, are not established. By understanding how this happens we may be able to design effective treatment for this problem. Our initial results indicate that virus induced asthma is different to asthma that is triggered by allergens. We plan to investigate what effect certain viruses have on the lungs of people with asthma by measuring cells and chemicals that are present in sputum. We will use recently developed technologies to accurately see what viruses are infecting these people, and then evaluate the role of treatment of virus induced asthma. This study will shed important light on potential causes of unstable asthma and the role that viral infection plays in this. It may also lead to new opportunities to develop treatments that are more effective in preventing and controlling asthma.Read moreRead less
We seek to gain a detailed understanding of how interactions between the West Nile virus proteins and host factors involved in the IFN response determine the outcome of virus infection. Better understanding of the mechanisms employed by this highly pathogenic virus to disable the mammalian host's IFN response will have wider implications for our understanding of other human diseases such as cancer, autoimmunity and provide new avenues for design of efficient antiviral and anticancer therapies.
Immune Cell Interactions And Cell Signalling Pathways Important For Rotavirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$343,812.00
Summary
Rotaviruses are the main cause of severe diarrhoea in Australian children, through infection of the gut cells that absorb food. This project aims to understand the effects of rotaviruses on the functioning and survival of these cells at the molecular level. It will similarly determine the effects of rotavirus infection on the immune cells. These studies will increase understanding of how rotaviruses cause disease, and assist in the development of drugs or improved vaccines against rotavirus.
Contribution Of Dendritic Cell Paralysis To The Immunosuppression Associated With Systemic Infections
Funder
National Health and Medical Research Council
Funding Amount
$490,051.00
Summary
The immune system fights viruses and other infections mobilising antibody-producing B cells and killer T cells. The B cells and killer T cells are recruited by specialysed cell of the immune system called Dendritic Cells (DC). The DC are distributed all over the body, where they play an immunosurveillance role: they constantly monitor their sorroundings for the presence of pathogens. When DC detect these pathogens they become activated . They capture the pathogen, break it into small pieces call ....The immune system fights viruses and other infections mobilising antibody-producing B cells and killer T cells. The B cells and killer T cells are recruited by specialysed cell of the immune system called Dendritic Cells (DC). The DC are distributed all over the body, where they play an immunosurveillance role: they constantly monitor their sorroundings for the presence of pathogens. When DC detect these pathogens they become activated . They capture the pathogen, break it into small pieces called antigens, and display these antigens on their surface, where they can be seen by helper T cells, which in turn mobilise the B cells, and by killer T cells. This chain of reactions initiates an immune response. The DC undergo profound changes after they detect pathogens. They stop monitoring their sorroundings, and concentrate on displaying to T cells the antigens that belonged to the pathogen that triggered their initial activation. Indeed, they do not respond to new pathogen encounters. In normal conditions few DC are activated by each pathogen encounter, so there are always enough DC ready to respond to new infections. However, there are situation that activate nearly all the DC at the same time. This can happen during sepsis (bacterial infection of the blood) and malaria. It has been recognised for a long time that these two conditions can be immunosuppressive they shut-down the immune system. Our previous work has demonstrated that this is in part due to the excessive number of DC that sepsis or malaria activate, leaving no more DC capable of responding to subsequent infections. This work has focused on the immediate effects of sepsis or malaria -within the first 24 hours or so; now we want to investigate the efffect of these conditions on the reconstitution of the DC network. We think this will help us to find treatments to restore immunocompetence a functional immune system- in sepsis or malaria patients.Read moreRead less
Generation And Maintenance Of Effective T Cell Memory In Peripheral Organs
Funder
National Health and Medical Research Council
Funding Amount
$336,767.00
Summary
Infectious diseases represent potentially life-threatening events. Immunity against re-infection relies on different types of memory immune cells that constantly patrol through the organism in search for invading agents. Recently, it has emerged that there exists an additional type of memory cells that permanently reside in peripheral tissues where they confer immediate immune protection. This project will examine the requirements for the generation and maintenance of this important cell type.
Regulation Of Subcellular Localisation Of Respiratory Syncytial Virus M Protein: Implications For Pathology
Funder
National Health and Medical Research Council
Funding Amount
$580,195.00
Summary
Respiratory syncytial virus (RSV) is the major cause of viral pneumonia in infants and the elderly, causing more deaths in winter than influenza. We have observed RSV M protein in the nucleus of infected host cells where it inhibits host cell transcription. We propose to investigate the regulation of nuclear localisation of M by phosphorylation and binding to cellular factors and its importance to RSV pathogenesis. The results will relate strongly to future drug and vaccine development.
Role Of Nucleocytoplasmic Trafficking Of Matrix Protein In RSV Infection
Funder
National Health and Medical Research Council
Funding Amount
$495,041.00
Summary
Respiratory syncytial virus (RSV) is the major cause of viral pneumonia in infants and young children throughout the world. By the age of 3, virtually every child has been infected by RSV at least once. RSV is also an important cause of pneumonia in the elderly and is estimated to cause more deaths each winter than influenza. In Australia, an estimated 100,000 infants are infected by RSV every year. In Victoria, RSV is the most common cause of all reported cases of respiratory tract disease, wit ....Respiratory syncytial virus (RSV) is the major cause of viral pneumonia in infants and young children throughout the world. By the age of 3, virtually every child has been infected by RSV at least once. RSV is also an important cause of pneumonia in the elderly and is estimated to cause more deaths each winter than influenza. In Australia, an estimated 100,000 infants are infected by RSV every year. In Victoria, RSV is the most common cause of all reported cases of respiratory tract disease, with an estimated annual cost of $1-4 million. Despite more than 40 years of research there is no vaccine to prevent RSV infection, and the only drug (ribavirin) licenced for treatment of RSV infection is expensive, difficult to administer, toxic, and of doubtful efficacy. We propose to examine one of the RSV proteins, the matrix protein (M). M is very important for virus propagation and is responsible for resultant cell injury. We have observed that M enters the cell nucleus (the location for all cellular DNA and RNA synthesis) where it appears to inhibit host cell RNA synthesis early in infection; later, it exits the nucleus in a step required for virus production in the cytoplasm. The signals that regulate transport of M into and out of the nucleus and the effect on the host cell leading to pathogenesis, are the focus of this proposal. The results of this study will be beneficial in many ways. Most importantly, we will gain knowledge about the processes underlying cell injury caused in RSV disease, which may lead to the identification of novel targets for intervention strategies.Read moreRead less
The Blood-Retinal Barrier - Modelling Mechanisms For Maintenance, Breakdown And Repair
Funder
National Health and Medical Research Council
Funding Amount
$394,310.00
Summary
We believe that breakdown of the barrier that separates the delicate nervous tissue of the eye from the bloodstream, the blood-retinal barrier, may be an early event in the development of age-related macular degeneration (AMD), now overall the commonest cause of blindness in Australia. We have recently demonstrated with the first scientific clinical trials to be conducted in the world that an injection of steroid into the jelly of the eye, or vitreous , of the steroid triamcinolone slows the gro ....We believe that breakdown of the barrier that separates the delicate nervous tissue of the eye from the bloodstream, the blood-retinal barrier, may be an early event in the development of age-related macular degeneration (AMD), now overall the commonest cause of blindness in Australia. We have recently demonstrated with the first scientific clinical trials to be conducted in the world that an injection of steroid into the jelly of the eye, or vitreous , of the steroid triamcinolone slows the growth of abnormal blood vessels in patients with wet AMD. In the current project, Prof Nick King, a cell biologist and viral immunologist, will collaborate with Dr Michelle Madigan, A-Prof Jan Provis, both experts in experimetnal AMD, and A-Prof Mark Gillies, a clinician-scientist specialising in AMD, to study how the treatment works using established animal and laboratory models of a damaged blood retinal barrier. We will be particularly interested in processes which are thought to critical in the development these diseases. We will also study newly described processes by which the junctions that seal the cells of the barrier together come apart. We will be interested not just in the cells that make the barrier, but also the effect of nearby cells that are thought to contribute to it. These studies will provide a solid foundation for the rationalisation of steroid treatment for AMD which can be expected to result in improved outcomes for our patients. The studies may also provide insights into how other barriers malfunction, such as the blood brain barrier which breaks down in Alzheimer s disease and multiple sclerosis.Read moreRead less