Modulation Of Leishmaniasis By The Proinflammatory Cytokines TNF
Funder
National Health and Medical Research Council
Funding Amount
$288,911.00
Summary
We have established a mouse model that has been genetically modified and cannot produce the cytokine tumour necrosis factor. This cytokine is secreted in the beginning of the inflammatory response. If these mice are infected with a parasite they are not able to heal the infection and die quickly. We can demonstrate that these mice cannot regulate the beginning inflammatory response and do not form a cellular infiltrate at the site of infection.
Deciphering The Epigenetic Code Of T Lymphocyte Stability In Disease
Funder
National Health and Medical Research Council
Funding Amount
$662,785.00
Summary
T lymphocytes defend against invading pathogens and establish immunological memory to protect us if the infection returns. As there are many different types of pathogens, T lymphocytes must be flexible in the way they respond to infection but also stable once they have decided on the appropriate type of response. This complex decision-making appears to be dictated by epigenetic changes to the chromatin state of the cell. This work will uncover epigenetic factors that maintain this balance to pro ....T lymphocytes defend against invading pathogens and establish immunological memory to protect us if the infection returns. As there are many different types of pathogens, T lymphocytes must be flexible in the way they respond to infection but also stable once they have decided on the appropriate type of response. This complex decision-making appears to be dictated by epigenetic changes to the chromatin state of the cell. This work will uncover epigenetic factors that maintain this balance to protect us against disease.Read moreRead less
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.
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
Type 2 Immunity: A Regulator Of Physiology, Tissue Repair And Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$640,210.00
Summary
Intestinal helminths (worms) have evolved together with humans and induce strong type 2 immune responses effective at eradicating the parasite, mediating tissue repair and modulating the gut microbiota. My research aims to decipher the roles of type 2 immunity in regulating intestinal health and promoting tissue repair. I also plan to determine how worm infection and type 2 immunity modulate the microbiota the impact of this on health, particularly obesity.
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
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.
Effects Of Natural Sequence Variation On Evasion Of Cytotoxic T Lymphocytes By Murine Cytomegalovirus.
Funder
National Health and Medical Research Council
Funding Amount
$553,167.00
Summary
Human cytomegalovirus persists for the life time of an infected person. It has many ways of achieving this, including interfering with the host immune response. This project seeks to explore this using a mouse model and murine CMV. Specifically we will focus on a set of viral genes that inhibit host recognition of virally infected cells. Sequence variation in these genes suggests that they function differently in different strains of virus: we will examine the consequences of this variation.
Age-dependent Regulation Of Type 2 Immunity By Dermal Innate Lymphoid Cells
Funder
National Health and Medical Research Council
Funding Amount
$609,281.00
Summary
Type 2 immune responses are critical for the defense against worm infections, but can also cause allergic reactions. How type 2 immunity is regulated is poorly understood. The aim of this application is to define the function of a newly discovered skin immune cell population, dermal type 2 innate lymphoid cell, in cutaneous worm infections and allergies. We anticipate that our studies will aid in the development of strategies to prevent or treat skin allergies and parasitic infections.
Understanding Immune Responses To Severe Influenza Virus Infection And Vaccination In Humans
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
During influenza virus infection, people acquire robust and long-lasting immunity. However, current influenza vaccines elicit only transient immunity. I will define optimal responses in different immune cell types after natural infection versus vaccination; understand why some people fail to generate protective antibodies to the vaccine; and identify key biomarkers aimed at reducing influenza disease impact in high risk groups. This work will improve future influenza vaccination regimens.