Role Of Cytomegalovirus Class I Homologue In Interference With Host NK Cell Responses - A Potential Antiviral Target
Funder
National Health and Medical Research Council
Funding Amount
$428,020.00
Summary
A common property of herpesviruses such as cytomegalovirus is their ability to establish lifelong infection in their hosts. In humans, cytomegalovirus infection can lead to tissue damage in normal individuals and may cause severe disease and even be fatal in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. The ability of these viruses to establish persistent infection and remain in asso ....A common property of herpesviruses such as cytomegalovirus is their ability to establish lifelong infection in their hosts. In humans, cytomegalovirus infection can lead to tissue damage in normal individuals and may cause severe disease and even be fatal in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. The ability of these viruses to establish persistent infection and remain in association with the host for its lifetime is a consequence of their capacity to subvert normal host immune responses. This is achieved by destroying or mimicking the functions of molecules and-or pathways critical to normal host defence mechanisms. The viral gene product under investigation is similar to a cellular protein critical for the ability of immune cells to kill foreign and-or infectious agents. We will investigate the mechanisms by which this viral gene product interferes with the host's first line of defence against viral pathogens. The proposed studies will improve our understanding of the strategies used by viruses to escape normal host immune responses and hence provide insights into the rational design of antiviral drugs and vaccines. Since the viral protein under investigation is similar to a cellular protein essential for the ability of immune cells to kill foreign or infectious agents, an improved understanding of the mechanisms of action of this protein will continue to improve our understanding of cellular events which play a crucial role in immune responses involved not only in control of infection, but also in tumour growth and transplant survival. Thus, the proposed studies will provide valuable insight towards the development of new therapies for pathological conditions associated with the above.Read moreRead less
The Role Of The Dendritic Cell Surface Molecule Clec9A In Dendritic Cell Subset Function And Dead Cell Recognition
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Dendritic cells (DC) are sentinels of the immune system. DC monitor the environment and regulate tolerance to self versus immunity to dangerous material. Different types of DC perform different jobs. We have identified a new surface molecule, Clec9A, on some mouse and human DC. We will investigate the function of Clec9A in the immune response. We will also use Clec9A to help unite mouse and human DC biology, since until now there have been few useful marker molecules common to both species.
Behavioural, Virological And Immunological Factors Influencing Hepatitis C Virus Infection In Injecting Drug Users
Funder
National Health and Medical Research Council
Funding Amount
$963,437.00
Summary
The hepatitis C virus (HCV) is a major public health problem affecting over 170 million people worldwide. In Australia an estimated 157,000 people have HCV and are at risk of serious disease, and 16,000 new infections occur each year. Treating HCV-related disease is expensive, and this healthcare burden is projected to grow significantly in coming years. Almost all new HCV infections in Australia occur among injecting drug users (IDUs), and despite our world-leading prevention programs, the viru ....The hepatitis C virus (HCV) is a major public health problem affecting over 170 million people worldwide. In Australia an estimated 157,000 people have HCV and are at risk of serious disease, and 16,000 new infections occur each year. Treating HCV-related disease is expensive, and this healthcare burden is projected to grow significantly in coming years. Almost all new HCV infections in Australia occur among injecting drug users (IDUs), and despite our world-leading prevention programs, the virus is spreading. Consensus is emerging that the best hope for control of HCV and related disease lies in a vaccine; our research will lay much of the groundwork for its development. The applicants' research to date shows that IDUs are being infected with HCV more frequently than previously assumed, that many carry multiple strains, and that dominant strains vary rapidly in individuals over time. These results reinforce the view that our prevention methods will not reduce infection rates and that current anti-viral treatments are not the solution. Nevertheless, we also found that some IDUs remain free of HCV infection despite risky behaviour with infected associates; intensive study of the immune functioning of these persistently non-infected individuals holds promise for vaccine development. In our proposed research, a collaboration of leading Australian epidemiologists, virologists and immunologists, we will recruit 210 young IDUs and follow them regularly for two years. Recruits will describe their social networks and nominate IDUs with whom they inject, provide blood samples and be interviewed about their behaviour at 3-month intervals. Individuals with recent and resolved HCV infection, change of dominant strain and lack of infection despite risky behaviour will be identified and their blood analysed for genetic factors that may be linked to immune protection. The outcomes will be crucial to the development and trialling of a vaccine against HCV.Read moreRead less
Role Of CD4 T Cells And APCs In The Induction And Maintenance Of An Effective Antitumor Response
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Many cancers are still untreatable by conventional therapies (surgery, chemotherapy and radiation). This includes malignant mesothelioma, a cancer associated with previous exposure to asbestos. Exposure can occur up to 30 years before the onset of this disease. The average time of survival for patients, from the time of diagnosis, is about nine months and the incidence of this disease is increasing. Novel therapies are therefore required to help alleviate this disease and perhaps eradicate it. I ....Many cancers are still untreatable by conventional therapies (surgery, chemotherapy and radiation). This includes malignant mesothelioma, a cancer associated with previous exposure to asbestos. Exposure can occur up to 30 years before the onset of this disease. The average time of survival for patients, from the time of diagnosis, is about nine months and the incidence of this disease is increasing. Novel therapies are therefore required to help alleviate this disease and perhaps eradicate it. Immunotherapy - using the body's own defence system to help fight cancer- is one potential form of new treatment. However we need to understand how the immune system and cancer normally interact with one another if we are to make rational decisions about the design of immunotherapies. We have established a laboratory model which allows us to investigate this interaction. We will determine which components of the immune system are required to eradicate cancer and at which stages of cancer growth they are most important. By understanding these pieces of the puzzle we may be able to tweak the system more appropriately or design vaccines that will be effective in at risk populations.Read moreRead less
The Role Of T Cell Receptor Avidity In Determining T Cell Repertoires And Responses
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
T cells are an essential component of the immune system. CD8 T cells, in particular, play a vital role in the immune response to viruses and tumors, predominantly via killing of virally infected cells and tumor cells, as well as the release of inflammatory mediators. T cells must be activated before they can mediate such anti-viral or anti-tumor effects and this activation occurs through the binding of pathogen or tumor fragments (peptides) by a receptor on the surface of T cells (T cell recepto ....T cells are an essential component of the immune system. CD8 T cells, in particular, play a vital role in the immune response to viruses and tumors, predominantly via killing of virally infected cells and tumor cells, as well as the release of inflammatory mediators. T cells must be activated before they can mediate such anti-viral or anti-tumor effects and this activation occurs through the binding of pathogen or tumor fragments (peptides) by a receptor on the surface of T cells (T cell receptor). Each individual has an entire repertoire of T cells with unique T cell receptors which interact with peptides with varying binding strengths. After stimulation of T cells by e.g. viral infection, a subset of the T cell repertoire will become expanded and dominate the anti-viral immune response. This study aims to investigate how, during a viral infection, the strength (or 'avidity') of the interaction between the T cell receptor and the peptide influences (i) whether or not a T cell clone is recruited into the immune response and, if so, its dominance over other clones within that response, and (ii) how efficiently a T cell is activated. It is anticipated that particular virus peptide-specific T cell populations with an overall high avidity will be better able to produce inflammatory mediators and kill infected cells compared to lower avidity T cell populations specific for a different virus peptide. It is also expected that the higher avidity populations will exhibit greater diversity of TCRs. Further, within peptide-specific populations, it is anticipated that the relatively high avidity T cell clones will dominate the specific response. This study will contribute to a greater understanding of factors contributing to T cell recruitment and activation. Armed with this knowledge we will be better able to design vaccines to elicit optimal T cell responses to viral infection.Read moreRead less
Cutaneous Inflammation, Bone Marrow Dendritic Cells, And Implications For Immune Responses And Immune Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$327,151.00
Summary
With inflammation of the skin due to excessive sun exposure or chemicals, biological signals are sent to the bone marrow where immune fighting cells are generated. However, the immune system must not overreact. We have measured bone marrow derived immune cells with reduced function following skin inflammation which we propose is part of homeostasis. We need to better understand how these cells are altered and for how long they are altered.
A successful vaccine prevents infection. For HIV infection all candidate vaccines thus far have failed. From the many HIV-1 infected individuals there are a very small percentage that do not progress to disease. For these infected subjects we hypothesise that their immune responses are much better preserved and hence they will have stronger antibody responses. We have geared up our laboratory to characterise these strong antibodies and use them in making a better HIV-1 vaccine.
The Effect Of Innate Immune Responses On The Induction Of Protective Immunity In Murine Typhoid Fever
Funder
National Health and Medical Research Council
Funding Amount
$136,500.00
Summary
Salmonella are important pathogens of humans causing diseases ranging from gastroenteritis, typhoid fever to arthritis. Like most if not all infections, the early interaction between the host and the bacterium is characterised by very non-specific symptoms. These non-specific symptoms arise because the so-called innate immune system is activated by the infection. The purpose of this grant is to establish whether these non-specific symptoms, caused by the release of immunological homrones called ....Salmonella are important pathogens of humans causing diseases ranging from gastroenteritis, typhoid fever to arthritis. Like most if not all infections, the early interaction between the host and the bacterium is characterised by very non-specific symptoms. These non-specific symptoms arise because the so-called innate immune system is activated by the infection. The purpose of this grant is to establish whether these non-specific symptoms, caused by the release of immunological homrones called cytokines, are essential to the development of an effective immune response which can protect against subsequent re-infection. This study has important implications for vaccines, of our understanding of how bacteria cause disease, and the role-capacity of the innate immune system in the development of immunity.Read moreRead less
Immunotoxic Effects Of Engineered Nanomaterials Used In The Australian Workplace
Funder
National Health and Medical Research Council
Funding Amount
$586,816.00
Summary
Certain engineered nanomaterials are more toxic than their bulk material forms. We urgently need the ability to re-engineer these nanomaterials to reduce their toxicity and potential health risks, but lack the necessary knowledge. This project directly addresses the NHMRC Strategic Initiative on Nanotechnology and Health, by providing essential information for designing safer nanomaterials from systemically studying the immune effects of metal oxide nanoparticles used in Australian industry.