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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.
I am a respiratory physician studying mechanisms of respiratory allergy and host defence against respiratory viruses. My research aims to develop new ways of treating airway inflammation in asthma and COPD.
Identification Of Host Restriction Factors That Block Respiratory Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$956,898.00
Summary
Following inhalation, respiratory viruses can infect and grow in airway epithelial cells. Although immune cells such as macrophages are also susceptible to infection, this is generally abortive and new viruses are not released. This project will identify proteins induced in macrophages that block respiratory viruses and prevent their spread in the airways. We will also define mechanisms by which some virulent strains overcome this block to grow in macrophages.
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
Use Of Mouse Models To Study Mechanisms Of Pathology In Viral Exacerbations Of COPD
Funder
National Health and Medical Research Council
Funding Amount
$411,960.00
Summary
We want to understand why cigarette smoke exposure worsens respiratory virus infections. People who smoke, or who have smoked in the past, or who are exposed to environmental (passive) smoke, get sicker than nonsmokers when they get a respiratory virus infection, such as a common cold or the flu. This is true for people of all age groups, but we don't know why smoke has this effect. We think it may be because smoke interferes with some aspects of the immune response. A particular focus of our re ....We want to understand why cigarette smoke exposure worsens respiratory virus infections. People who smoke, or who have smoked in the past, or who are exposed to environmental (passive) smoke, get sicker than nonsmokers when they get a respiratory virus infection, such as a common cold or the flu. This is true for people of all age groups, but we don't know why smoke has this effect. We think it may be because smoke interferes with some aspects of the immune response. A particular focus of our research is chronic obstructive pulmonary disease. COPD is a serious lung disease which generally occurs in people who have smoked for many years. However, many COPD patients stopped smoking many years ago. COPD patients are especialy at risk of serious outcomes if they get a respiratory infection (known as an acute COPD exacerbation) and patients with COPD exacerbations use a lot of health care resources. There are no effective drugs to prevent or treat COPD exacerbations. We are currently using a mouse model of smoke exposure and virus infection to do this research, which is a much faster and more ethical approach than using humans in research. We believe that we will get a better understanding of how smoke affects the immune response to infection. This is likely to contribute to the development of better drugs for COPD exacerbations and other types of smoking related lung disease.Read moreRead less
Soluble Inhibitors Of Influenza Virus In The Airway Fluids Of Mice, Ferrets And Humans.
Funder
National Health and Medical Research Council
Funding Amount
$404,803.00
Summary
This study will characterize the ability of soluble proteins in airway secretions to recognize and destroy influenza viruses. As many of our insights regarding influenza pathogenesis are derived from studies in animal models, we will characterize the importance of proteins in airway fluids from mice and ferrets, as well as from humans. These findings will be of particular importance when assessing the relevance of particular animal models to understanding human disease.
Inhibition Of IFN-?/? By Human Metapneumovirus And The Induction Of Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$605,251.00
Summary
The newly isolated human metapneumovirus (hMPV) causes significant respiratory illness in infants, young children and the elderly. The virus can persist long-term and may predispose individuals to chronic lung disease. This proposal aims to determine the mechanisms by which hMPV infection causes respiratory disease, with a view to improving treatments and preventing disease.
Stealth Liposomes And SiRNA For The Treatment Of Respiratory Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$528,793.00
Summary
Respiratory infections caused by Influenza and Respiratory syncytial virus cause significant hospitalisations and deaths within the community. For example, RSV causes around 1000 hospital admissions of young children a year and there is no cure or vaccination. Therapies are limited and toxic. We will develop and test a novel therapy based on gene silencing to specifically target viral genes, and combine this with our novel drug delivery system for better treatment of these diseases.
Exploring The Role Of Respiratory Virus Infections In Childhood Asthma Exacerbations
Funder
National Health and Medical Research Council
Funding Amount
$596,649.00
Summary
The PEAK study will explore the reasons children get worse asthma symptoms when they get colds. These reasons examined include the asthma medications taken (or not taken), allergies and exposure to allergens and the type of virus involved. The study follows the children over the whole school term and uses a new way to sample virus by collecting it in the breath, this is more comfortable than old methods and can be done at home.
Kunjin Virus Replicon-based Vaccine Vectors: New Developments And Applications
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The project is aimed towards further development of a unique gene expression and delivery system based on self-replicating RNA (replicon) of the nonvirulent Australian flavivirus Kunjin (KUN). A number of improvements in the design of KUN replicon vectors aimed to increase their efficiency and to optimize them for production of heterologous gene products with desired terminal sequences are proposed. Also proposed are improvements in the current KUN replicon packaging system and development of ne ....The project is aimed towards further development of a unique gene expression and delivery system based on self-replicating RNA (replicon) of the nonvirulent Australian flavivirus Kunjin (KUN). A number of improvements in the design of KUN replicon vectors aimed to increase their efficiency and to optimize them for production of heterologous gene products with desired terminal sequences are proposed. Also proposed are improvements in the current KUN replicon packaging system and development of new packaging systems for production of large amounts of virus-like particles (VLPs) containing KUN replicon RNA enclosed in KUN coat proteins for use as potential vaccines. The vaccine potentials of the curent and newly developed KUN vectors and VLPs will be evaluated in mice using respiratory syncytial virus as a model. An entirely new direction proposed in this application is generation of chimeric fowlpox virus-KUN replicon vectors which will combine the advantages of both systems and may result in the generation of an ultimate vaccine vector.Read moreRead less