Current vaccines rely on immune components in the blood. We are taking a different approach, which focuses on immunity at the body surfaces. These are the areas where pathogens first gain access to the body and we have shown that immune cells in these regions are far more potent than those that need to be recruited from the circulation.
The Impact Of Influenza A Virus PB1-F2 Protein On Host Immunity And The Potential For Therapeutic Targeting
Funder
National Health and Medical Research Council
Funding Amount
$317,076.00
Summary
The 1918 influenza virus pandemic resulted in 50 million deaths globally and there is potential for new pandemics, such as the predicted H5N1 Bird Flu . Exact causes of such devastating lethality are not fully identified. Newly discovered influenza A virus (IAV) PB1-F2 protein is present in nearly all highly pathogenic IAVs and promotes virus virulence. This study will further examine the way in which PB1-F2 impacts the host, revealing potential therapeutic targets to lessen disease burden.
A specialised set of T lymphocytes called Mucosal Associated Invariant T (MAIT) cells react against bacteria and yeast, and reside at mucosal sites where the body's immune defences are most easily breached, e.g. respiratory tract and intestinal mucosa. This study investigates the role of MAIT cells in both protection and pathology in bacterial infections. Controlling MAIT cells could help in treating these conditions.
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
My basic science and translational research centres around elucidation of the function of the mucosal barrier in preventing infection, inflammation and development of cancers, and how defects in this barrier lead to these diseases.
Cell Surface Mucins In Gastrointestinal Infection And Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$591,967.00
Summary
Mucosal tissues, such as the gastrointestinal and respiratory tracts, are the most common site of infectious disease. We have found that the cells in these tissues produce molecules on their surface, known as mucins, that protect from infection. In the case of chronic infection the mucins prevent the inflammation that underlies the development of cancer. In this project we will be exploring the mechanisms by which mucins prevent infection and inflammation.
Vaccines that deposit memory T cells within the lung, gut and genital tract hold enormous therapeutic potential, as these mucosal surfaces are major portals of entry into the body for many viruses. However, the accumulation of large numbers of T cells within the mucosal tissue may increase the number of target cells for T cell trophic viruses (eg HIV) to infect. We will explore factors that result in the generation of mucosal memory T cells that are resistant to virus infection.
Long Lived, Virus Resistant Resident Memory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$415,218.00
Summary
Vaccines that deposit memory T cells within the lung, gut and genital tract hold enormous therapeutic potential, as these mucosal surfaces are major portals of entry into the body for many viruses. However, the accumulation of large numbers of T cells within the mucosal tissue may increase the number of target cells for T cell trophic viruses (eg HIV) to infect. We will explore factors that are important in the generation of mucosal memory T cells that are also resistant to virus infection.