Defining The Mechanisms That Regulate Effective Long-term Anti-viral Immunity
Funder
National Health and Medical Research Council
Funding Amount
$547,315.00
Summary
Human cytomegalovirus (HCMV) is a common human pathogen which normally causes a mild or even asymptomatic infection. However, in immunocompromised individuals, HCMV causes severe disease whose manifestations include chorioretinitis, interstitial pneumonia and hepatitis. Similarly, in neonates lacking a fully mature immune system, HCMV causes severe morbidity. Vaccines that protect against HCMV induced cytomegalic inclusion disease have been designated Level I (most favourable) due to the predict ....Human cytomegalovirus (HCMV) is a common human pathogen which normally causes a mild or even asymptomatic infection. However, in immunocompromised individuals, HCMV causes severe disease whose manifestations include chorioretinitis, interstitial pneumonia and hepatitis. Similarly, in neonates lacking a fully mature immune system, HCMV causes severe morbidity. Vaccines that protect against HCMV induced cytomegalic inclusion disease have been designated Level I (most favourable) due to the prediction that they could save lives and prevent life-long disability. Similarly, therapies that prevent and-or reduce HCMV reactivation will significantly improve the prognosis of transplant and AIDS patients. The murine CMV (MCMV) infection model has provided important insights as to how the immune system controls infection, and the mechanisms utilized by the virus to circumvent these processes. The design of effective therapies and vaccines requires a thorough understanding of the mechanisms required to generate and maintain long-lasting anti-viral responses. The studies outlined in this proposal aim to define the impact of specific components of the immune system n the generation, maintenance and effectiveness of anti-viral immunity. The well characterized MCMV model will be used to address these issues.Read moreRead less
Improving Adaptive Anti-viral Responses: A Key To Eliminating Persistent Viral Infection
Funder
National Health and Medical Research Council
Funding Amount
$402,391.00
Summary
Cytomegalovirus (CMV) can cause a persistent infection that can result in adverse clinical outcomes. Our previous work established that suboptimal adaptive immunity is responsible for viral persistence. This proposal will define the defect in adaptive immunity, its causes and how to improve it. The understanding gained from the proposed studies will provide crucial information for the development of improved anti-viral therapies and vaccines.
Mechanisms Of Virally-induced Immunosuppression: Effects On DC-NK Networks
Funder
National Health and Medical Research Council
Funding Amount
$566,308.00
Summary
Cytomegalovirus (CMV) infection induces immunosuppression that often results in adverse clinical outcomes. Our previous work established that dendritic cells (DC), cells involved in the initiation of immune responses, are a principle target for CMV. This proposal will test the hypothesis that CMV-induced immunosuppression is mediated by viral interference with DC. Understanding the mechanisms involved in the induction of immunosuppression is a crucial step towards developing better therapies.
In Vivo Responses To Pathogen-derived Mediators Of Acute Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$94,250.00
Summary
Sepsis causes large numbers of deaths worldwide. It is not known why some patients tolerate an infection and fully recover, while other patients with an equivalent infection are highly vulnerable to severe illness and death from sepsis. Heart failure is a common underlying condition in sepsis. This research will focus on how an infection can cause sudden cardiac death. It will have implications for care of patients with severe infection and also sudden infant death syndrome.
Apoptosis Amongst Specific And Bystander T Cells In Chronic Bacterial Infection
Funder
National Health and Medical Research Council
Funding Amount
$317,545.00
Summary
When an infection occurs the immune cells (lymphocytes) proliferate in order to initiate and expand the immune response. If the body had no mechanisms to limit proliferation, the numbers of cells would soon overwhelm the body. Working with simple protein antigens rather than infection, other workers have found that once T lymphocytes have been activated and the immune response triggered, they soon undergo a process of self destruction called apoptosis. However, during infection, if the limits to ....When an infection occurs the immune cells (lymphocytes) proliferate in order to initiate and expand the immune response. If the body had no mechanisms to limit proliferation, the numbers of cells would soon overwhelm the body. Working with simple protein antigens rather than infection, other workers have found that once T lymphocytes have been activated and the immune response triggered, they soon undergo a process of self destruction called apoptosis. However, during infection, if the limits to lymphocyte proliferation are imposed before the infecting bacterium is eliminated, full expression of immunity does not occur and chronic infection may result. We believe that this contributes to the chronicity of such infections as tuberculosis and leprosy. We also suspect that, during infection, not only protective T lymphocytes proliferate, but also nonspecific bystander cells. This exaggerates the problem of lymphocyte proliferation and adds to immunopathology (immune damage). We have established an animal model of chronic bacterial infection in order to study how apoptosis is induced in T lymphocytes and how its adverse effects may be overcome. We hypothesize that apoptosis may be induced by one or more of a number of mechanisms, and that they may differ for the specific protective cells and the bystander cells. Once we understand the mechanisms apoptosis of specific lymphocytes may be prevented without harming the body. This has the potential to open new areas of immunotherapy (manipulating the immune response) of these diseases.Read moreRead less
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
Understanding The Mechanisms Of Cytomegalovirus Induced Immunosuppression: Relevance To Viral Immunotherapies
Funder
National Health and Medical Research Council
Funding Amount
$467,310.00
Summary
Cytomegalovirus (CMV), measles and human immunodeficiency virus (HIV) are the three main human pathogens known to induce immunosuppression. The down-regulation of immune responses that characterizes a state of immunosuppression imparts the infecting pathogens the opportunity to escape immune surveillance and thus maximizes their chances to survive within their host, to replicate and be transmitted as required. The generalized immunosuppression caused by viral infection is often associated with s ....Cytomegalovirus (CMV), measles and human immunodeficiency virus (HIV) are the three main human pathogens known to induce immunosuppression. The down-regulation of immune responses that characterizes a state of immunosuppression imparts the infecting pathogens the opportunity to escape immune surveillance and thus maximizes their chances to survive within their host, to replicate and be transmitted as required. The generalized immunosuppression caused by viral infection is often associated with secondary infections with unrelated viral and-or bacterial pathogens, and as such represents a serious clinical problem. In humans, cytomegalovirus infection can cause tissue damage in normal individuals and may cause severe disease and even mortality in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and patients undergoing chemotherapy. The severe complications that occur in the latter group of patients result from the combined effects of pre-existing and viral induced immunosuppression that often lead to severe secondary opportunistic infections. In transplant recipients however, CMV induced immunosuppression, in the absence of secondary infections, can be beneficial and has been associated with improved transplant outcome. The central aim of the work in the current proposal is to investigate the cellular and viral mechanisms involved in cytomegalovirus induced immunosuppression. The proposed studies will improve our understanding of viral interference with host immune responses and hence will be relevant to understanding the pathogenesis of CMV infection in humans and more importantly will provide critical insights into the rational design of suitable antiviral drugs and vaccines.Read moreRead less
The Role Of Apoptosis In Pathogenesis And Immunology Of Salmonella Infections
Funder
National Health and Medical Research Council
Funding Amount
$276,988.00
Summary
Salmonellae are important human pathogens in developed and developing countries. The most severe salmonella disease, typhoid fever, is becoming more difficult to treat because of increasing antibiotic resistance. In addition, current vaccines only provide short-term protection. The studies in this proposal are designed to answer important questions about immunity against typhoid fever, including how this immunity is provoked, and the direct and indirect causes of pathology in the disease. The fo ....Salmonellae are important human pathogens in developed and developing countries. The most severe salmonella disease, typhoid fever, is becoming more difficult to treat because of increasing antibiotic resistance. In addition, current vaccines only provide short-term protection. The studies in this proposal are designed to answer important questions about immunity against typhoid fever, including how this immunity is provoked, and the direct and indirect causes of pathology in the disease. The focus of this project is the induction of host cell apoptosis, an important virulence mechanism shared by many bacteria and viruses. The research will have direct application to human typhoid and may lead to novel therapies and improved vaccines for typhoid fever.Read moreRead less
Modulation Of Apoptosis By Cytomegalovirus: Analysis Of New Mechanisms To Interfere With Cytomegalovirus-induced Disease
Funder
National Health and Medical Research Council
Funding Amount
$697,084.00
Summary
Apoptosis, or programmed cell death is an essential process in developmental and homeostatic control of complex biological systems. In addition to these primary house keeping roles, apoptosis provides a powerful defence mechanism against invading pathogens, such as viruses, since it allows early elimination of infected cells from the host. A basic property of herpesviruses is their ability to establish persistent infection and remain in association with the host for its lifetime. This strongly u ....Apoptosis, or programmed cell death is an essential process in developmental and homeostatic control of complex biological systems. In addition to these primary house keeping roles, apoptosis provides a powerful defence mechanism against invading pathogens, such as viruses, since it allows early elimination of infected cells from the host. A basic property of herpesviruses is their ability to establish persistent infection and remain in association with the host for its lifetime. This strongly underlines their success at reaching an accommodation with the immune system's anti-apoptotic mechanisms. The central hypothesis of this project is that herpesviruses, such as murine and human cytomegalovirus, encode proteins that interfere with cell death pathways thereby circumventing host defence so that viral replication and dissemination can proceed. Thus, the aims are to identify and characterise cytomegalovirus proteins that modulate apoptosis. These studies will improve our understanding of the control of apoptosis during viral infection, especially as caused by cytomegaloviruses. Human cytomegalovirus (HCMV) is a pathogen able to cause significant morbidity and mortality in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. Hence, the proposed studies will allow the elucidation of molecular mechanisms that may be relevant to the pathogenesis of HCMV in man and will provide insights into the rational design of suitable antiviral drugs and vaccines. Understanding viral mechanisms of host immune evasion continues to improve our understanding of complex cellular pathways. Therefore, given that abnormal regulation of apoptosis is implicated in the development of degenerative conditions, cancer and autoimmune disease, the proposed studies will provide valuable insight towards the development of new therapies for these pathological conditions.Read moreRead less
Regulation Of TNF Receptor Expression By Omega-6 And Omega-3 Polyunsaturated Fatty Acids
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
This project looks at two major molecules which our body generates in trying to combat infections, a protein called tumor necrosis factor (TNF) and a fatty acid called arachidonic acid. In some cases the persistent production of elevated amounts of these molecules leads to highly crippling and debilitating diseases , such as rheumatoid arthritis, which pose a huge burden to our community. To develop medication to combat these diseases be it either vaccination or antiinflammatory drugs, there is ....This project looks at two major molecules which our body generates in trying to combat infections, a protein called tumor necrosis factor (TNF) and a fatty acid called arachidonic acid. In some cases the persistent production of elevated amounts of these molecules leads to highly crippling and debilitating diseases , such as rheumatoid arthritis, which pose a huge burden to our community. To develop medication to combat these diseases be it either vaccination or antiinflammatory drugs, there is a need to clearly define key components of the inflammatory response. Since TNF acts through a receptor we propose that a critical issue in the regulation of this inflammatory response is the changes in the expression of these receptors on cells of the immune system. Our preliminary work suggests that lipid molecules such as arachidonic acid (omega-6 fat) interacts with phagocytic cells and causes drammatic changes to the expression of this receptor. Our research proposal will look at this in more detail and place the observation into perspective in terms of parameters of the inflammatory reaction and associated diseases. Furthermore this concept will be examined in relation to the protective effects which the omega-3 fats found in fish oil have on these inflammatory diseases.Read moreRead less