The immune system employs a variety of strategies to combat parasites including viruses. One of them is cytolytic lymphocytes, cells that can recognize and destroy virus-infected target cells. These cells use, besides other molecules, enzymes called granzymes to kill target cells by inducing suicide in them. We intend to investigate if those granzymes can protect cytolytic lymphocytes themselves from being infected by viruses and turned into viral factories. We are going to use a model of a natu ....The immune system employs a variety of strategies to combat parasites including viruses. One of them is cytolytic lymphocytes, cells that can recognize and destroy virus-infected target cells. These cells use, besides other molecules, enzymes called granzymes to kill target cells by inducing suicide in them. We intend to investigate if those granzymes can protect cytolytic lymphocytes themselves from being infected by viruses and turned into viral factories. We are going to use a model of a natural infection, ectromelia, mouse pox. Mouse pox is fatal in resistant strains of mice if the genes for the two dominant granzymes are deleted. This indicates that granzymes are essential for fighting this viral disease. We will explore in which cells of the immune system granzymes are expressed and whether virus entry into a cell can actually trigger their expression. Furthermore, we will investigate how the granzymes inhibit virus infection within the infected cell to determine whether the mechanisms involved resemble those used by cytolytic lymphocytes in killing of target cells (i.e. degradation of DNA and mitochondrial damage), or whether they represent entirely new facets of granzyme function. Finally, using viruses from a number of different families, we will establish whether these functions of granzymes also contribute to protection from other viral infections. An understanding of the role of these granzymes in the innate immune response, i.e. before antigen specific T cell and antibody responses are fully activated, is of great significance as it may allow us to manipulate this particular anti-viral response and thus enhance survival and reduce morbidity in viral infections.Read moreRead less
Understanding And Modulating Hyperinflammation Caused By Influenza Viruses
Funder
National Health and Medical Research Council
Funding Amount
$425,048.00
Summary
In humans, highly pathogenic influenza A virus (IAV) infections can be fatal, as the disease is untreatable with available vaccine or anti-viral drugs. My fellowship aims to advance our knowledge of the mechanisms by which the immune system induces and regulates inflammation during IAV infection, which can be both helpful and detrimental in fighting the infection. This is critical for identifying and developing new therapies for severe IAV infections in the future.
Influenza A Virus PB1-F2 Protein: A Putative Virulence Factor And Initiator Of Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$474,718.00
Summary
Influenza virus produces a protein of undefined function called PB1-F2. Infection of mice with virus expressing PB1-F2 from virulent strains causes severe lung inflammation, while PB1-F2 from milder seasonal viruses does not. We will examine how PB1-F2 influences virulence of human influenza in the ferret, which exhibits the same illness as humans. This work will help understand the disease severity of newly evolved influenza viruses of humans and the role of PB1-F2 in mediating this.
The Biology Of Ross River Virus And Its Cellular Receptor
Funder
National Health and Medical Research Council
Funding Amount
$252,750.00
Summary
Ross River virus (RRV) causes a principally rheumatic disease in up to 8000 Australian annually. The disease is severe at onset comparable to that suffered by patients with osteoarthritis awaiting hip replacement. However, the disease usually resolves within 6 months. This grant intends to continue our studies on how and why RRV causes disease and develop an understanding of why only 1 person in 20 infected with RRV actually develops disease. We believe RRV arthritis is cause by RRV persisting i ....Ross River virus (RRV) causes a principally rheumatic disease in up to 8000 Australian annually. The disease is severe at onset comparable to that suffered by patients with osteoarthritis awaiting hip replacement. However, the disease usually resolves within 6 months. This grant intends to continue our studies on how and why RRV causes disease and develop an understanding of why only 1 person in 20 infected with RRV actually develops disease. We believe RRV arthritis is cause by RRV persisting in specific white blood cells residing within joint tissues. The grant intends to exploit the recent observation that to infect cells RRV uses a receptor, which human cells normally use to bind to collagen. Armed with this new information we intend to unravel how RRV can persist despite the patient making good antibody responses against the virus, and determine whether high levels of this receptor predispose to disease. The ultimate goal for these studies is the identification of potential new treatments for this and perhaps other arthritic diseases caused by viruses. We have also recently identified a new virus in seals that is related to RRV, but fortunately appears not to pose a health threat to humans. However, we intend to test whether this new virus uses the same receptor as RRV and begin to explore using computer technology some of mutations these viruses would need before they could successfully infect humans.Read moreRead less
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
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
Regulation Of Antiviral And Antiinflammatory Responses By MTNF: Key Role Of Reverse Signaling By Host And Viral TNFR
Funder
National Health and Medical Research Council
Funding Amount
$568,501.00
Summary
New and re-emerging viral infections continue to pose a major problem. We have recently discovered a hitherto unrecognized process that the body uses to regulate its response to infection. Some viruses have evolved to target this process, underscoring its importance. We will study 2 virus models, poxvirus and influenza A, to understand how this process works during infection. We will also examine the potential to exploit this process to block pathology and influence recovery from infection.