Heterosubtypic T Cell-inducing Vaccines For Influenza In Humans
Funder
National Health and Medical Research Council
Funding Amount
$352,307.00
Summary
Bird flu virus poses a large risk to the world if it mutates to become easily spread between people. If this occurs vaccines will be made to the mutated strain but there will be a time lag before these are available. We have been working on a novel vaccine that induces protective T cell immunity to parts of the virus that are common to all influenza strains and will be effective against any new virus. Our information from animal models will be used to create a human vaccine of this type .
Pathophysiological Significance Of Reverse Signaling Through Membrane TNF
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They coordinate the activities of leukocytes and therefore are important in the host response against infections. However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural killer cells, in two stages: first, the cytokine is exposed on the surfac ....Cytokines are molecules produced by cells that take part in immune and inflammatory responses. They coordinate the activities of leukocytes and therefore are important in the host response against infections. However, overproduction of some cytokines, particularly tumour necrosis factor, seems to cause the deleterious consequences. Tumour necrosis factor is made by cells, particularly macrophages, T lymphocytes and natural killer cells, in two stages: first, the cytokine is exposed on the surface of the cell and then it is 'clipped off' and released as a smaller, soluble form. In either form it can interact with specific receptors on other cells and, in this way, change the cells' activities. We believe that binding of tumour necrosis factor receptors to the cytokine while it is in its membrane form can also send a message backwards, into the cell bearing the tumour necrosis factor. This process, known as reverse signalling, then changes the activity of this cell. In this project we will investigate this phenomenon in detail. The results will be extremely relevant to new methods of treatment of diseases, that rely either on 'masking' tumour necrosis factor by administering soluble forms of its receptor or on blocking the release of the soluble form of the molecule from the surface of the cell. Our work will enable us to understand the consequences of these approaches more fully. We will also be looking at the role of the membrane form of tumour necrosis factor in a model of infectious disease. Influenza virus is responsible for a great deal of morbidity and mortality around the world. We, and others, have shown, in a mouse model, that some cells in the lungs make tumour necrosis factor during the course of viral pneumonia. Here we will determine whether the membrane form of this cytokine plays a role in clearing virus or causing some of the complications of this disease. This also may have relevance to other inflammatory and infectious disease.Read moreRead less
While current influenza vaccines blunt winter epidemics, they must be updated frequently to keep up with virus mutation and they do not protect against pandemics caused by new flu viruses (such as bird flu). This program will define how flu virus interacts with the immune system to generate immunity mediated particularly by “killer” T cells. We will use this knowledge to develop and evaluate vaccines that induce long-lasting T-cell immunity that can protect against both seasonal and pandemic flu ....While current influenza vaccines blunt winter epidemics, they must be updated frequently to keep up with virus mutation and they do not protect against pandemics caused by new flu viruses (such as bird flu). This program will define how flu virus interacts with the immune system to generate immunity mediated particularly by “killer” T cells. We will use this knowledge to develop and evaluate vaccines that induce long-lasting T-cell immunity that can protect against both seasonal and pandemic flu.Read moreRead less
Mechanisms Regulating Antigen Presentation During Primary And Recall Responses Of T Cells Following Pathogen Infection
Funder
National Health and Medical Research Council
Funding Amount
$441,364.00
Summary
The primary role of the immune system is the containment of pathogens, cancer cells and infections. This depends on generating long-lived memory CD8+ killer T lymphocytes. Generally this process is achieved efficiently in acute infections in which the pathogen grows relatively rapidly. However, pathogens such as herpes viruses and tuberculosis grow more slowly, fail to efficiently activate the killer T cells such that they elude the immune system and are never completely removed from the body. T ....The primary role of the immune system is the containment of pathogens, cancer cells and infections. This depends on generating long-lived memory CD8+ killer T lymphocytes. Generally this process is achieved efficiently in acute infections in which the pathogen grows relatively rapidly. However, pathogens such as herpes viruses and tuberculosis grow more slowly, fail to efficiently activate the killer T cells such that they elude the immune system and are never completely removed from the body. These latter infections result in persistent or chronic infections. Our work will endeavour to unravel the mechanisms that underlie how a killer T cell is effectively activated and the factors that contribute to failure of these cells to be similarly activated in a persistent infection. The central aim of the studies described in this proposal is to understand the mechanisms utilized by different pathogens to generate the diverse population of memory killer T cells that allow us to respond to the plethora of pathogens we might encounter every day. These studies will improve our understanding of how antigen presenting cells and killer T lymphocytes ensure an immune response is maintained and may identify checkpoints that could be targeted to modulate the immune response when it goes wrong.Read moreRead less
Control Of Influenza A Virus Infection By Gamma Interferon-inducible Mediators
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Influenza A virus is a cause of morbidity and mortality worldwide. Due to antigenic shift and drift of the virus, including the emergence of pandemic strains, humans are often challenged with strains different from those to which they have been exposed by vaccination or prior infection. This has historically resulted in very serious increases in illness and death. The most severe pandemic of influenza A virus that has occurred in modern times was the worldwide pandemic of 1918-1920 when over 20 ....Influenza A virus is a cause of morbidity and mortality worldwide. Due to antigenic shift and drift of the virus, including the emergence of pandemic strains, humans are often challenged with strains different from those to which they have been exposed by vaccination or prior infection. This has historically resulted in very serious increases in illness and death. The most severe pandemic of influenza A virus that has occurred in modern times was the worldwide pandemic of 1918-1920 when over 20 million deaths occurred. Development of new interventive strategies to combat virus-related illness therefore remains critical to complement the present vaccine approach. For this, a clear understanding of the host's response to influenza virus infection is essential. For its part, the immune system has at its disposal several strategies to combat influenza A virus. How the immune system deals with the virus is controlled by a complex network of interactions involving cells, cell surface molecules, soluble mediators termed cytokines and chemokines. One cytokine, interferon-gamma, seems to be a key player in the body s ability to get rid of the virus. Here, we are trying to understand how interferon-gamma does this. We believe that this cytokine causes specific immune cells to produce other molecules, such as indolamine 2,3-deoxygenase (IDO) and chemokines, and that it is these molecules that control virus growth. We do not know whether these molecules stop virus growth directly or by creating the right conditions for this. We are interested in understanding the sequence of events that is started by interferon-gamma and ends in the clearance of virus from the lungs. To study the immune response to influenza virus, we use a mouse model that reproduces most features of the human disease. By understanding the events that lead to effective virus clearance in this disease, it may be possible to design new ways in which to combat this problematic infection in humans.Read moreRead less
Molecular Basis Of T Cell Receptor Bias In Viral Immunity
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Viral infection results in the activation and proliferation of T cells that eradicate infected cells. Recognition of infected cells is meditated by presentation and recognition of viral protein fragments via specific cell surface receptors. This proposal plans to examine the factors that determine the diversity of the immune response and the consequences of such diversity on anti-viral immunity. This has implications for the development of vaccines.
Cytolytic Mechanisms Required For Virus Elimination.
Funder
National Health and Medical Research Council
Funding Amount
$698,567.00
Summary
Viruses provoke devastating disease. The immune system kills cells that are infected with viruses. To do this, immune cells release granules that are packaged with different killer molecules. It is unknown which killer molecules participate over the course of an immune response to virus. Here, we will investigate this process for cells that are infected with influenza A virus and herpes simplex virus. This study will allow the design of strategies to limit widespread damage inflicted by viruses.
Interplay Of Innate And Adaptive Immunity To Influenza A Virus
Funder
National Health and Medical Research Council
Funding Amount
$555,693.00
Summary
Influenza is an acute febrile respiratory illness caused by influenza virus infection, and may trigger potentially life-threatening complications especially in the young and elderly. Immunity against influenza virus involves integration of the innate and adaptive immune system. We will use cutting-edge 2-photon microscopy to determine the orchestration of innate and adaptive immune cell interactions during viral infection. Results may provide for enhanced therapeutic or protective measures.