A Novel Viral Modifier Of TNF Family Receptor Signalling: Elucidation Of Mechanisms Of Action
Funder
National Health and Medical Research Council
Funding Amount
$453,727.00
Summary
Over millions of years, viruses have evolved a great number of strategies to allow them to subvert the effectiveness of the host response. We have discovered that one of these viral strategies seems designed to block the synthesis of an important anti-viral factor, called tumour necrosis factor. In this project, we aim to work out how the viral factor blocks tumour necrosis factor production inside the cell, at the level of the molecules involved. The second aspect of this project concerns the i ....Over millions of years, viruses have evolved a great number of strategies to allow them to subvert the effectiveness of the host response. We have discovered that one of these viral strategies seems designed to block the synthesis of an important anti-viral factor, called tumour necrosis factor. In this project, we aim to work out how the viral factor blocks tumour necrosis factor production inside the cell, at the level of the molecules involved. The second aspect of this project concerns the identification of the types of cells and responses which the viral factor acts upon to manipulate the host response. We reason that this information will improve our understanding of how tumour necrosis factor production is regulated and the significance of this type of response in virus infection and physiology, more generally. The application of this research will be to aid the design of better drugs for the treatment of many conditions where tumour necrosis factor production contributes significantly to pathology, eg rheumatoid arthritis and autoimmunity. In some conditions, it may be a therapeutic advantage to selectively turn on tumour necrosis factor, eg for treatment of infections or cancer.Read moreRead less
Identification Of Innate Receptors For Influenza Viruses
Funder
National Health and Medical Research Council
Funding Amount
$398,156.00
Summary
Innate immune mechanisms are vital components of early host defence against pathogens. In this proposal we will define novel components of the innate immune system that first recognize influenza virus as foreign and act to destroy the virus. We will target novel receptors present in lung fluids and on the surface on innate immune cells of the respiratory tract.
An Exploration Of The Balance Between West Nile Virus Pathogenesis And Immune System Mediated Control
Funder
National Health and Medical Research Council
Funding Amount
$325,442.00
Summary
West Nile Virus (WNV) is a mosquito transmitted infectious disease that is emerging globally. Infection can lead to the development of fatal encephalitis and currently there is no vaccine available for human use. Killer T cells, a component of the immune system, are essential for viral clearance from the brain. This project aims to further explore WNV pathogenesis and whether killer T cells can be utilized to keep the infection localised and prevent the spread of the virus to the brain.
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
Crystallographic Studies Of Non-canonical Peptides Binding To MHC Class I Molecules.
Funder
National Health and Medical Research Council
Funding Amount
$489,750.00
Summary
Virus infected cells and cancer cells are recognised and eliminated from our body by specialised cells called T-cell lymphocytes. This recognition process is the key step in the immune response and some fundamental questions in immunology are centred on the nature of this process. At the molecular level, the recognition is mediated by the specific interaction between proteins on the surface of the cells. On the T-cell lymphocyte, the T-cell receptor (TCR) binds specifically to a protein called t ....Virus infected cells and cancer cells are recognised and eliminated from our body by specialised cells called T-cell lymphocytes. This recognition process is the key step in the immune response and some fundamental questions in immunology are centred on the nature of this process. At the molecular level, the recognition is mediated by the specific interaction between proteins on the surface of the cells. On the T-cell lymphocyte, the T-cell receptor (TCR) binds specifically to a protein called the MHC on the surface of the target cell. The target cell can be a cancer cell, or an infected antigen presenting cell (specialised cells in the body which present protein fragments (peptides) on their surface via MHC). The structure of a TCR and TCR-MHC have been solved in terms of the shape of the molecules at atomic resolution, bringing detailed information on how these two proteins interact with each other. In this proposal the structural basis of antigen presentation and recognition in cell-mediated immunity will be determined by three-dimensional structures of different peptides on MHC by x-ray crystallography. Cell surface antigen presentation by MHC molecules is crucial for initiating the cellular immune response against invading pathogens and cancer. This proposal encompasses a combined biochemical, immunological, and biophysical approach to understand the range of ligands which can bind to MHC which are subsequently recognised by the TCR. To understand the antigenic properties of modified peptides at the structure level, the x-ray structure of MHC with modified bound synthetic peptides will be determined.Read moreRead less
Regulation Of Antiviral And Antiinflammatory Responses By MTNF: Key Role Of Reverse Signaling By Host And Viral TNFR
Funder
National Health and Medical Research Council
Funding Amount
$568,501.00
Summary
New and re-emerging viral infections continue to pose a major problem. We have recently discovered a hitherto unrecognized process that the body uses to regulate its response to infection. Some viruses have evolved to target this process, underscoring its importance. We will study 2 virus models, poxvirus and influenza A, to understand how this process works during infection. We will also examine the potential to exploit this process to block pathology and influence recovery from infection.
Structural Investigations Of Bacterial Evasion Of IgA Mucosal And Systemic Immunity
Funder
National Health and Medical Research Council
Funding Amount
$488,812.00
Summary
Nose, throat and skin infections are often caused by streptococcal and staphylococcal bacteria, known as Strep Throat and Golden Staph. Infections can be life-threatening in newborns, the elderly or individuals with weak immune systems. These bacteria make proteins bind and inactivate immune proteins. Our research examines the structural basis for bacterial interactions with a key immune system protein (an antibody called IgA) and may lead to new prevention and treatment strategies.