Mechanisms Regulating Establishment Of Persistent Herpesvirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$511,446.00
Summary
Herpesviruses are a major cause of disease worldwide and are amongst the most successful human pathogens, with some viruses infecting more than 80% of the world's population. This group of viruses persist and reactivate in hosts and induce immunosuppression.The control of herpesviruses infections thus represents an important clinical goal. Understanding the mechanisms involved in the induction of viral persistence and immunosuppression is a crucial step towards developing better therapies.
Characterising And Visualising Cross-presenting Dendritic Cells Following Cutaneous Vaccinia Infection
Funder
National Health and Medical Research Council
Funding Amount
$415,682.00
Summary
Live imaging of cells within lymphoid organs provides a valuable tool allowing insight into how immune responses are initiated. Utilising novel reagents we will visualise and define these events following cutaneous infection with vaccinia virus.
Biological Function Of The Chemokine Receptor 6 Expression On B Cells
Funder
National Health and Medical Research Council
Funding Amount
$241,500.00
Summary
The correct movement of cells is important for the defence of the body against micro-organisms. White blood cells have to arrive quickly at the site of an infection and information about this infection has to be spread. White blood cells that navigate the body are using molecules on their surface termed as receptors which help them to detect the scent of their target. One of these receptors is located on white blood cells that produce antibodies and enables these cells to migrate to appropriate ....The correct movement of cells is important for the defence of the body against micro-organisms. White blood cells have to arrive quickly at the site of an infection and information about this infection has to be spread. White blood cells that navigate the body are using molecules on their surface termed as receptors which help them to detect the scent of their target. One of these receptors is located on white blood cells that produce antibodies and enables these cells to migrate to appropriate tissues . We want to know more about the biological role of this receptor and its functions during the immune response to pathogens. It would be of significant importance to understand the impact of these cell surface receptors in detail because this could open the possibility to new therapies of infectious diseases and chronic inflammation.Read moreRead less
Chronic infections and cancers are major causes of global disease burden. Harnessing the immune system to combat these diseases has proven difficult and cumbersome to date. We invented a new technology to boost the ability of the immune system to fight chronic infections such as AIDS and Hepatitis C. This involves using someone�s own blood treated with sets of short proteins. We term this therapy Overlapping Peptide Pulsed Autologous CelLs (OPAL). This shows great promise in robust animal models ....Chronic infections and cancers are major causes of global disease burden. Harnessing the immune system to combat these diseases has proven difficult and cumbersome to date. We invented a new technology to boost the ability of the immune system to fight chronic infections such as AIDS and Hepatitis C. This involves using someone�s own blood treated with sets of short proteins. We term this therapy Overlapping Peptide Pulsed Autologous CelLs (OPAL). This shows great promise in robust animal models. We now propose to refine this technique in animals in preparation for human clinical trials.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
It is feasible to sequence patient genomes but we need to know more about how genetic variants cause complex disease. We have sequenced genomes from patients with immune deficiency and will test the idea that genetic variation causes consistent changes in particular white blood cells, thus providing a bridge between genomic information and clinical diagnosis. Outcomes will include more accurate diagnosis, better understanding of immunity, and a strategy for using whole genome information.
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
Developmental-associated Dysregulation Of Innate Anti-microbial Immunity In Early Life As A Determinant Of Susceptibility To Atopic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$570,334.00
Summary
Previous NHMRC-sponsored research from the applicants has demonstrated that one of the strongest risk factors for subsequent development of asthma is having chest infections during infancy that are so severe that they trigger symptoms of fever and wheeze. It is not known what predisposes susceptible infants to these severe infections, and this project will attempt to define the mechanisms of susceptibility.
Innate lymphoid cells (ILCs) are found in the lining of the intestine and are part of the intricate crosstalk between the food we eat, good bacteria, epithelial cells and other immune cells. Without ILCs, the body is susceptible to infections through the intestinal tract. I will investigate the signals from nerve cells that control that activity of ILCs during infection to give us insights into pathways that activate ILCs in situations where they are reduced or inactive.
Antigen Dose And TCR Repertoire In CD8+ T Cell Immunodominance Hierarchies
Funder
National Health and Medical Research Council
Funding Amount
$558,920.00
Summary
The CD8+, or killer , T lymphocytes (white blood cells) are the hit men of immunity, recirculating continually around the body to eliminate other cells that are dangerous because they are cancerous or infected with a virus. A major difficulty is that killer T cells also exert selective pressures that cause viruses and tumours to mutate and thus avoid immune control. This is a particularly serious problem for RNA viruses that readily mutate as they divide. These include the human immunodeficiency ....The CD8+, or killer , T lymphocytes (white blood cells) are the hit men of immunity, recirculating continually around the body to eliminate other cells that are dangerous because they are cancerous or infected with a virus. A major difficulty is that killer T cells also exert selective pressures that cause viruses and tumours to mutate and thus avoid immune control. This is a particularly serious problem for RNA viruses that readily mutate as they divide. These include the human immunodeficiency virus (HIV) that causes AIDS and, while the mutations that are most important with influenza viruses are those that modify viral surface proteins recognized by antibodies, such T cell escape mutants can also be a problem with influenza. The other reason why there is particular interest in promoting CD8+ T cell-mediated immunity to influenza is that the killer T cells are very cross-reactive. We have shown that vaccination approaches that prime mouse CD8+ T cells to resist influenza A viruses circulating currently in humans will also protect against the highly lethal, and dangerous H5N1 bird 'flu. The present flu vaccines only stimulate antibodies, so there is interest in the possibility of a major re-design. The CD8+ T cells recognize tiny elements (peptides) of the virus or tumour bound in the tip of our own transplantation, or class I major histocompatibility complex (MHCI) molecules. These pMHCI complexes are called epitopes. The focus here is on the use of novel genetic engineering strategies to find out how, when the virus mutates to disrupt the major epitopes seen by killer T cells, other minor epitopes can be abnormally emphasized in a way that promotes effective immune control. As we work on this with the relatively simple and safe influenza model we will concurrently develop strategies that may be of value in HIV and tumour immunity. Solving this problem could prove to be a substantial advance in the design of vaccines and immunotherapy approaches.Read moreRead less