The Role Of Cross-reactive T Cells In Severe Lung Disease Following Viral Respiratory Infections
Funder
National Health and Medical Research Council
Funding Amount
$1,003,390.00
Summary
Why do some patients clinically deteriorate at a greater rate than others during acute respiratory viral infections despite similar or identical clinical management? One explanation is the reactivation immunity towards ubiquitous viruses that then go on to cross-react against the new respiratory pathogen leading to an overly aggressive and destructive response in the lung. We will examine this potential of existing anti-viral immune responses to exacerbate disease in lung transplantation, as suc
Costimulatory Mechanisms For Enhancing CD8 T Cell Responses During An Acute Respiratory Infection
Funder
National Health and Medical Research Council
Funding Amount
$438,750.00
Summary
Following an infection, a person's immune system responds to fight the pathogen. One of the most important consequences of the immune response to an infectious disease is the establishment of memory to that particular disease so that a person is able to clear the same pathogen faster upon subsequent exposures. This memory is due to specific cells called memory lymphocytes. One subset of these cells are called CD8+ T cells and these are important for controlling and clearing viral infections. New ....Following an infection, a person's immune system responds to fight the pathogen. One of the most important consequences of the immune response to an infectious disease is the establishment of memory to that particular disease so that a person is able to clear the same pathogen faster upon subsequent exposures. This memory is due to specific cells called memory lymphocytes. One subset of these cells are called CD8+ T cells and these are important for controlling and clearing viral infections. New vaccine strategies are aimed at improving CD8 T cell responses so that they are more effective at fighting diseases such as HIV which causes AIDS and Hepatitis C virus. The mechanisms which lead to long lived memory CD8 T cells are not well understood. This research will characterise the function of genes involved in activating CD8 T cells and producing more memory CD8 T cells. The influenza model will be used as it is a well characterised model for studying anti-viral immunity. This project involved studying the mechansims of known genes involved in CD8 T cell responses to influenza. Also the discovery of new genes which are involved in CD8 T cell memory will be identified and characterised using new novel technologies, such as ENU mutagenesis, that only now are able to be utilised since the mouse genome (DNA) has been sequenced. This research will provide a basis for design of new and more effective vaccines.Read moreRead less
Generation And Maintenance Of Effective T Cell Memory In Peripheral Organs
Funder
National Health and Medical Research Council
Funding Amount
$336,767.00
Summary
Infectious diseases represent potentially life-threatening events. Immunity against re-infection relies on different types of memory immune cells that constantly patrol through the organism in search for invading agents. Recently, it has emerged that there exists an additional type of memory cells that permanently reside in peripheral tissues where they confer immediate immune protection. This project will examine the requirements for the generation and maintenance of this important cell type.
Memory CD4 T Cells That Harbour The Reservoir Of Latent HIV Infection: Their Antigen Specificity, Function And Frequency Of Antigen-driven Reactivation
Funder
National Health and Medical Research Council
Funding Amount
$453,782.00
Summary
Current antiretroviral therapy for HIV successfully suppresses virus production, but does not completely eliminate the virus from the body. This project will provide essential information on memory CD4 T cells that retain HIV in a latent DNA form. Memory CD4 T cells can be very long-lived, and these latently infected memory cells can give rise to virus during treatment interruption. We will use a novel method to identify which memory CD4 T cells contain latent HIV DNA.
Cellular Activation And Apoptosis In Response To Foreign Cytoplasmic DNA
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
Viruses are simple organisms. They grow within cells, needing host cell proteins for their replication. Viruses have only a few proteins of their own, and evolve rapidly to change these. It is therefore challenging for the immune system to identify viral infections. Recently it has been recognised that the genetic material of viruses (DNA or RNA) is detected by the immune system. A novel pathway for recognition of viral double stranded DNA is emerging. The genetic material of mammalian cells (DN ....Viruses are simple organisms. They grow within cells, needing host cell proteins for their replication. Viruses have only a few proteins of their own, and evolve rapidly to change these. It is therefore challenging for the immune system to identify viral infections. Recently it has been recognised that the genetic material of viruses (DNA or RNA) is detected by the immune system. A novel pathway for recognition of viral double stranded DNA is emerging. The genetic material of mammalian cells (DNA) is found within the membrane-bound nucleus of the cell. The presence of DNA outside the nucleus in the cytoplasm is abnormal, and is detected as an indication of viral infection. This causes either death of the cell, or activation to produce anti-viral molecules. We have identified a protein from the cytoplasm of cells which binds specifically to DNA. This protein, X is found in association with foreign DNA within 5 minutes of it being introduced into the cell. In this project we propose to confirm that X recognises foreign DNA and initiates cellular activation or death. Other molecules to which X binds during this process will be identified. This project is relevant to a number of problems in health and disease as well as biotechnology. In both gene therapy and biotechnology, DNA is introduced into cells in order to allow those cells to make specific proteins. The cell sees the introduced DNA as a potential viral infection, and it responds in ways which limit the production of the desired proteins. Lupus is an autoimmune disease with high levels of DNA in circulation. X is proposed as a protein involved lupus in mouse models. We suggest that DNA taken up by cells is recognised by X and this contributes to the disease. Understanding the means by which DNA is recognised in the cytoplasm may allow the development of much more efficient processes for gene therapy and protein production in biotechnology, and more effective lupus and antiviral therapies.Read moreRead less
Understanding Rapid T-cell Clearance By The Liver: A Critical Step Towards Improved Liver Transplantation.
Funder
National Health and Medical Research Council
Funding Amount
$412,134.00
Summary
The liver has paradoxical properties: it is the site of effective immune responses to pathogens, but under some circumstances, it is known to induce harmless immune responses. Poor responses can be beneficial in a transplantation setting because, in the absence of immunosuppressive drugs, liver transplants are more readily accepted than other organ allografts. Not only are liver transplants well accepted, they can induce secondary acceptance of kidney or heart grafts from the same donor that wou ....The liver has paradoxical properties: it is the site of effective immune responses to pathogens, but under some circumstances, it is known to induce harmless immune responses. Poor responses can be beneficial in a transplantation setting because, in the absence of immunosuppressive drugs, liver transplants are more readily accepted than other organ allografts. Not only are liver transplants well accepted, they can induce secondary acceptance of kidney or heart grafts from the same donor that would otherwise be rejected. However, this ability of the liver to induce unresponsiveness may allow some viruses to persist, particularly , Hepatitis B and C. Four in every five patients infected with hepatitis C develop a chronic disease due to the inability of the immune system to clear the virus. Although it is known that white blood cells enter the liver and become unresponsive, little is known about the mechanisms that prevent an effective response. The CIA s work has been at the forefront of liver immunology and transplantation by demonstrating that the architecture and vasculature of the liver, and therefore the type of unique cellular interactions taking place within it, are essential to gain an understanding of its unique immunological properties. Using the CIB s unique protocols for solid-organ transplantation in rodents, we will provide evidence for a new mechanism that occurs at very early stages after antigen encounter in the liver. We propose to unravel this mechanism using well characterised transgenic mouse models and advanced analytical technology. We will determine the role of this mechanism in liver transplantation. Our preliminary data point to a very high chance of success. This project will have important implications for transplantation studies and for the development and treatment of food allergies and chronic hepatitis C and other of immune-mediated liver diseases.Read moreRead less
Regulation Of Viral Latency In Gamma-herpesvirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$258,000.00
Summary
The cost to public health from herpesvirus infection is enormous. The gamma-herpesviruses chronically infect more than 95% of the world's population. This group of viruses induce a state of immunosuppression that cause down-regulation of immune responses. This allows the virus the opportunity to evade the immune system and thus survive within the host. The gamma-herpesviruses do not generally cause serious disease in normal individuals but reactivation of gamma-herpesviruses can cause severe dis ....The cost to public health from herpesvirus infection is enormous. The gamma-herpesviruses chronically infect more than 95% of the world's population. This group of viruses induce a state of immunosuppression that cause down-regulation of immune responses. This allows the virus the opportunity to evade the immune system and thus survive within the host. The gamma-herpesviruses do not generally cause serious disease in normal individuals but reactivation of gamma-herpesviruses can cause severe disease, even mortality, in individuals with an immature or a compromised immune system. Viral reactivation is a major complication of immunosuppressive diseases such as HIV (which currently affects more than 45 million people) and in transplant recipients. The virally-induced changes in the host cells can result in the development of secondary infections, post-transplantation lymphoproliferative disease and even the development of tumours. The central aim of the studies described in this proposal is to understand the cellular and viral mechanisms regulating how the virus is maintained in the host. These studies will improve our understanding of how antigen presenting cells and CD8+ T lymphocytes ensure an immune response is maintained and may identify critical targets to facilitate the rational design of antiviral drugs and vaccines.Read moreRead less
Host-virus Interactions That Define The Outcome Of Anti-viral T Cell Responses: Relevance To Viral Persistence
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Infection with human cytomegalovirus (hCMV) is normally resolved without symptomatic evidence of infection. However, severe hCMV disease can occur in immunocompromised patients in which the manifestations of disease include chorioretinitis, interstitial pneumonia and hepatitis. In immunologically immature children, congenital infection results in cytomegalic inclusion disease (CID). CID in infants causes severe neurological sequelae resulting in mental retardation, deafness and blindness. Vaccin ....Infection with human cytomegalovirus (hCMV) is normally resolved without symptomatic evidence of infection. However, severe hCMV disease can occur in immunocompromised patients in which the manifestations of disease include chorioretinitis, interstitial pneumonia and hepatitis. In immunologically immature children, congenital infection results in cytomegalic inclusion disease (CID). CID in infants causes severe neurological sequelae resulting in mental retardation, deafness and blindness. Vaccination against hCMV induced cytomegalic inclusion disease has been designated Level I (most favourable) due to the prediction that it could save lives and prevent life-long disability. Given the essential nature of CD8 T cells in CMV control and the high prevalence of CMV in society, it will be crucial to develop a vaccine capable of eliciting an efficacious T cell response which develops lasting memory. We hypothesise that mCMV has evolved mechanisms for generating an appropriate T cell response involved in viral control and the establishment of a persistent infection. The central aim of the work in the current proposal is to investigate the cellular and viral mechanisms involved in the generation of cytomegalovirus specific T cells. The proposed studies will improve our understanding of the generation of anti-viral T cell responses and hence will be relevent to further our understanding of the role of T cells in human infection. More importantly the results will provide critical insights into the rational design of suitable antiviral drugs and vaccines.Read moreRead less
In Vivo Imaging Of Virus-specific T Cell Responses In The Skin
Funder
National Health and Medical Research Council
Funding Amount
$332,258.00
Summary
Effective vaccination against many viral infections such as Herpes Simplex Virus (HSV) may be achieved by directing the cells of the immune system to specific sites in the body where they can lie in wait against the disease. To direct the immune system in this way, we must first understand how immune cells orchestrate themselves in tissues. This project will utilise advanced imaging techniques to study immune cells in real time to understand how they protect against viral infections in the skin.
A Novel Strategy To Enhance T Cell-mediated Immunity To Vaccine Antigens
Funder
National Health and Medical Research Council
Funding Amount
$234,592.00
Summary
Globally there are about 33 million people living with HIV. The disease has already resulted in 23 million deaths and 2.5 million people are newly infected each year. Similarly, TB kills nearly 2 million people every year and infects about 1% of the worldÍs population every year. A vaccine is the best and also likely the only long-term solution for HIV/TB disease prevention. This research proposal looks at novel strategies to increase the efficacy of vaccines for diseases such as HIV/TB.