Understanding The Role Of Chemokine Receptor Modulation In T Cell Trafficking
Funder
National Health and Medical Research Council
Funding Amount
$391,650.00
Summary
This research will begin to determine the significance of changes in the amount of recently-discovered proteins on the surface of cells called T lymphocytes. These cells control immune responses and move throughout the body to do this. Sometimes, they are activated inappropriately and cause diseases like asthma, arthritis and multiple sclerosis. It is therfore important to understand how the movement of these cells through the body is controlled. A better understanding of this process shuld allo ....This research will begin to determine the significance of changes in the amount of recently-discovered proteins on the surface of cells called T lymphocytes. These cells control immune responses and move throughout the body to do this. Sometimes, they are activated inappropriately and cause diseases like asthma, arthritis and multiple sclerosis. It is therfore important to understand how the movement of these cells through the body is controlled. A better understanding of this process shuld allow us to design better ways to control it, thereby controlling the negative aspects of T cell activation.Read moreRead less
Chemokine And Chemokine Receptor Regulation Of T Lymphocyte Traffic To Lymph Nodes
Funder
National Health and Medical Research Council
Funding Amount
$195,691.00
Summary
The movement of white blood cells from the bloodstream into the tissues is a key component of how we defend ourselves against infection and cancer, and also develop unwanted illnesses such as allergy. In particular, the migration of cells into lymph nodes is a critical step in the development of an efficient immune response. Surprisongly little is known about the control of this important cell trafficking process. In this research, the signals that control the movement of white blood cells are b ....The movement of white blood cells from the bloodstream into the tissues is a key component of how we defend ourselves against infection and cancer, and also develop unwanted illnesses such as allergy. In particular, the migration of cells into lymph nodes is a critical step in the development of an efficient immune response. Surprisongly little is known about the control of this important cell trafficking process. In this research, the signals that control the movement of white blood cells are being studied, notably a specialised family of immunological hormones, known as chemokines. Our initial studies suggest that chemokines are indeed the factors which control the traffic of the most important cell type - T cells, into lymph nodes. This research will examine how the activity of specific chemokines controls the influx of particular groups of T cells and subsequently determines the characteristics of the overall immune response taking place in the lymph node.Read moreRead less
Immunopathogenesis Of West Nile Virus Encephalitis - Requirement For Interferon-gamma-dependent Soluble Mediators
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Flaviviruses transmitted by arthropods cause considerable illness and death world-wide by their propensity to cause encephalitis. In August 1999, an outbreak of West Nile virus (WNV) encephalitis occurred in New York for the first time, indicating that these viruses are spreading beyond endemic areas. However, the mechanisms by which these viruses kill people are not at all clear. How the immune system deals with them is controlled by a complex network of interactions involving cells and soluble ....Flaviviruses transmitted by arthropods cause considerable illness and death world-wide by their propensity to cause encephalitis. In August 1999, an outbreak of West Nile virus (WNV) encephalitis occurred in New York for the first time, indicating that these viruses are spreading beyond endemic areas. However, the mechanisms by which these viruses kill people are not at all clear. How the immune system deals with them is controlled by a complex network of interactions involving cells and soluble mediators such as cytokines, chemokines, and nitric oxide, many induced or modulated by the cytokine, inteferon-gamma. Evidence suggests that these agents together influence both the types of cells that are mobilised to eradicate virus and also disease outcomes. Our hypothesis is that the host's own immune system is inadvertently responsible for encephalitis through an over-vigorous attempt to destroy the infecting virus, resulting in damage to the brain. To study WNV encephalitis, we are using a mouse model developed in this laboratory that reproduces the features of human disease. Another strain of these mice has the gene for interferon-gamma (IFN) inactivated or 'knocked out', so they cannot respond in the conventional way to virus infection. This mouse survives WNV infection significantly better than normal mice and becomes immune. Therefore we will compare cellular and soluble mediator responses of these mice during WNV infection to those of normal mice. We will also delete specific cell types making interferon-gamma in normal mice, as well as transfering such cells into knockout mice. Experiments will indicate which cell types are responsible and when particular components cause most damage. Thus, we will better understand how interferon-gamma recruits cells that mediate immune brain damage in this model. By understanding the events that lead to death in encephalitis, it may be possible to prevent or ameliorate them by means of immune intervention.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
Modulation Of HIV-1 Latency In Primary CD4 T Cells By Chemokines And Dendritic Cells
Funder
National Health and Medical Research Council
Funding Amount
$380,167.00
Summary
Although treatment of HIV using antiretroviral drugs has dramatically improved outcome the presence of latent infection in long lived T cells has so far prevented cure of HIV infection. This study examines the roles of chemokines (proteins that control cell migration) and a special type of infection fighting cell, the dendritic cell, in generating latent infection in resting T cells. These studies could potentially identify new ways to treat and potentially cure HIV infection.
Critical Role Of TNF In Host-virus Interactions And Outcome Of Infection: Involvement Of Reverse Signalling Through MTNF
Funder
National Health and Medical Research Council
Funding Amount
$496,500.00
Summary
Cytokines are molecules produced by cells that take part in the immune response. They coordinate the activities of leukocytes and are important in the host response to virus infections. For their part, viruses have evolved strategies to try and evade the host response. The analysis of these strategies in the context of a viral infection will lead to a better understanding of the immune system and host-virus interactions. Tumour necrosis factor is a cytokine made by specific leukocytes, in two st ....Cytokines are molecules produced by cells that take part in the immune response. They coordinate the activities of leukocytes and are important in the host response to virus infections. For their part, viruses have evolved strategies to try and evade the host response. The analysis of these strategies in the context of a viral infection will lead to a better understanding of the immune system and host-virus interactions. Tumour necrosis factor is a cytokine made by specific leukocytes, in two stages: First, the cytokine is exposed on the surface of the cell and then it is clipped off and released as a soluble form. In either form it can interact with specific receptors on other cells and, in this way, change the cells' activities. We have found 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 and constitutes a major new route through which information transfer can occur. In this project we will characterize the biological changes that result from reverse signalling in specific types of leukocytes. We will be looking at the role of membrane tumour necrosis factor in two separate models of viral disease. The first is influenza pneumonia that is responsible for a great deal of morbidity and mortality worldwide. The second is a model of poxvirus infection (mousepox) that mimics the disease smallpox in humans. Human poxvirus infections are on the rise (e.g. monkeypox) and there is an increased threat of smallpox as a weapon of bioterrorism. Mousepox is a good model for the study of generalized viral infections and is also an excellent example of a virus that encodes proteins specifically designed to interfere with host tumour necrosis factor. Our studies will focus on the role of this cytokine in host-virus interactions and the outcome of infection.Read moreRead less