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
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.
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.
Towards Improved Respiratory Outcomes In Preterm Infants Through Rapid And Effective Aerosalisation Of Medication To The Lung
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
Babies born premature are greatest at risk from increasingly common respiratory illnesses. It is possible that delivering a medication by aerosol will be the most effective method of treatment. For premature babies that need breathing support, inhaled medication could improve care. For highly infectious respiratory illnesses such as RSV, with no vaccines available, we need to protect babies very early in life. I will use an established lamb model to test fast medication delivery to the lungs.
Nuclear Transport In Health And Disease; Towards Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$851,980.00
Summary
This research fellowship will enable new therapeutic approaches to viral disease and cancer that target the transport process. I have already licenced an inhibitory molecule for Dengue virus which is progressing towards the clinic. I will now extend my research into a vibrant translational program of developing anti-viral (HIV, Respiratory Syncytical Virus, VEEV) as well as anti-cancer agents that will represent realistic therapeutic options in the near future.
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.
Oxidised Mannan As A Novel Adjuvant To Vaccinate Against Mucosal Infections
Funder
National Health and Medical Research Council
Funding Amount
$150,000.00
Summary
Most pathogens invade via the mucosal surfaces. However, current vaccines, which are delivered by injection, are poor at inducing mucosal immunity. An ideal vaccine would comprise a defined protein antigen combined with a suitable adjuvant which could be administered intranasally or orally. Protective antigens have been defined for a number of infections but suitable adjuvants have been elusive. We showed that mannan, a complex carbohydrate from yeast, oxidatively linked to protein antigens can ....Most pathogens invade via the mucosal surfaces. However, current vaccines, which are delivered by injection, are poor at inducing mucosal immunity. An ideal vaccine would comprise a defined protein antigen combined with a suitable adjuvant which could be administered intranasally or orally. Protective antigens have been defined for a number of infections but suitable adjuvants have been elusive. We showed that mannan, a complex carbohydrate from yeast, oxidatively linked to protein antigens can be used as an adjuvant for mucosal IgA and other classes of antibody. Given to mice intranasally, antigen coupled to mannan markedly enhanced production of IgA, IgG1 and IgG2a in serum, and IgA in lung, tears, vaginal secretions, saliva and gut. We have confirmed this for a number of known or putative protective antigens. In addition, both the Th1 and Th2 arms of the lymphocyte response were activated. We have demonstrated protection against P. gingivalis (cause of periodontitis and associated with premature birth and cardiovascular disease) in a mouse lesion model. However, before commercial interests will commit themselves, we need to demonstrate protection against viral infections and in other sites like lungs and gut. Three infection models where IgA has been shown to protect are already set up and can realistically produce results in 1 year. 1. Rotavirus is the major cause of severe infantile gastroenteritis in humans and animals world wide. The latest (live) vaccine was withdrawn because of side effects. We have established a model with Simian rotavirus causing an acute self-limiting disease in infant mice. Adult females will be immunised with mannan linked to killed virus preparations, mated and passive protection of their offspring will be assessed. Preliminary evidence links rotavirus infection with the onset of type 1 diabetes. If this is confirmed, there will be an opportunity to test the vaccine against diabetes. 2. Influenza: IN infection of mice with flu virus is a well established model. Mice will be immunised IN with mannan coupled to haemagglutinin-neuraminidase purified from egg-grown virus. They will be challenged IN with influenza virus and virus titrated in lung homogenates. Neutralising antibody in serum and lung washings will essayed. 3. Respiratory syncytial virus: RSV is the commonest cause of bronchiolitis and pneumonia in infants for which there have been unsuccessful attempts to produce a vaccine. F and G membrane glycoproteins have been shown to protect mice against IN infection, and they will be used coupled to mannan to vaccinate mice against intranasal challenge.Read moreRead less
Assembly Functions Of Respiratory Syncytial Virus Matrix Protein
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Respiratory syncytial virus (RSV) is the single most important cause of lower respiratory infections (pneumonia and bronchiolitis) in young infants. In addition to the morbidity of RSV infection itself, it is well established that symptomatic RSV infection in infancy predisposes to asthma later in life. As all infants are infected by RSV at least once by age 2 yrs, this virus represents a major public health problem. Additionally, re-infection by RSV is increasingly being recognized as a cause o ....Respiratory syncytial virus (RSV) is the single most important cause of lower respiratory infections (pneumonia and bronchiolitis) in young infants. In addition to the morbidity of RSV infection itself, it is well established that symptomatic RSV infection in infancy predisposes to asthma later in life. As all infants are infected by RSV at least once by age 2 yrs, this virus represents a major public health problem. Additionally, re-infection by RSV is increasingly being recognized as a cause of severe lower respiratory disease in the elderly and in immunocompromised patients. The goal of this research is to understand better the mechanisms used by RSV to replicate itself in mammalian cells. Information from this work could be used to design novel antiviral drugs to treat RSV, and novel attenuating mutations that may assist in developing live RSV vaccines. The research focuses on a key viral protein, the matrix (M) protein, which is involved in many steps in virus replication. We aim to understand how M protein interacts with other components of the virus (specifically, envelope proteins) to orchestrate virus assembly. To coordinate assembly of new virus particles, M protein binds to portions of virus envelope glycoproteins and to RSV nucleocapsids (the internal machinery of the virus), bringing them together at the cell membrane. The protein-protein interactions which are responsible for these functions of RSV M protein will be determined.Read moreRead less
Activation Of The Respiratory Syncytial Virus Fusion Protein
Funder
National Health and Medical Research Council
Funding Amount
$582,072.00
Summary
Respiratory Syncytial Virus (RSV) is the most important viral cause of respiratory tract disease in both infants and the elderly. However, there are few available options for control, whether by vaccination or therapeutic intervention. This proposal investigates the way RSV infects cells. A clearer understanding of the molecular basis of this process should provide potential targets for new drugs that can block this process and new insights for the generation of vaccine candidates.