Development Of Novel Vaccine Strategies To Prevent Genital Tract Chlamydial Infection
Funder
National Health and Medical Research Council
Funding Amount
$408,556.00
Summary
Genital tract chlamydial infection is the most common bacterial sexually transmitted disease world wide with 4-5 million cases occurring annually throughout the world. The incidence of chlamydial infection is increasing in the Australian population. The majority of infections in women are asymptomatic and, if untreated, go on to cause pelvic inflammatory disease, ectopic pregnancy and infertility. These conditions can be life threatening and are a significant public health cost. In the proposal ....Genital tract chlamydial infection is the most common bacterial sexually transmitted disease world wide with 4-5 million cases occurring annually throughout the world. The incidence of chlamydial infection is increasing in the Australian population. The majority of infections in women are asymptomatic and, if untreated, go on to cause pelvic inflammatory disease, ectopic pregnancy and infertility. These conditions can be life threatening and are a significant public health cost. In the proposal we will develop novel vaccine strategies, involving both intranasal immunisation and immunisation by direct application to the skin, to induce protection against genital tract chlamydial infection. These studies will lay the basis for human trials of a vaccine to prevent what is now the most common STD in Australia. Such a vaccine to target this chronic infection would represent a major advance in preventive healthcare for the maintenance of good health.Read moreRead less
Innate Immunity And Chlamydia Infection: Bacterial:epithelial Cell Cross-talk At The Mucosal Surface.
Funder
National Health and Medical Research Council
Funding Amount
$593,340.00
Summary
Chlamydial infections are the most common sexually transmitted disease in Australia. Infection induces short term immunity that is only partially protective. Furthermore, in many infected individuals the immune response causes inflammation of the fallopian tubes leading to pelvic inflammatory disease, ectopic pregnancy and infertility. In these individuals the initial chlamydial infection may not be cleared and a chronic infection may develop that can be reactivated, perhaps many times, contribu ....Chlamydial infections are the most common sexually transmitted disease in Australia. Infection induces short term immunity that is only partially protective. Furthermore, in many infected individuals the immune response causes inflammation of the fallopian tubes leading to pelvic inflammatory disease, ectopic pregnancy and infertility. In these individuals the initial chlamydial infection may not be cleared and a chronic infection may develop that can be reactivated, perhaps many times, contributing to the ongoing inflammatory response. Evidence from in vitro studies suggests that antibiotics routinely used to treat Chlamydia infection may actually contribute to the development of chronic infection. The stage of menstrual cycle at the time of exposure and oral contraceptive use can also influence susceptibility to infection suggesting that sex hormones influence infection outcomes. The innate or early immune response to infection by reproductive tract epithelial cells, the target cells of chlamydial infection, is believed to initiate the pro-inflammatory immune responses that will develop in some individuals following primary infection, however very little is known regarding this early epithelial cell immune response. In the proposed studies we will use reproductive tract epithelial cell lines, freshly isolated epithelial cells and cervical biopsy explant cultures to define this early innate immune response to chlamydial infection. Using gene-profiling techniques we will identify the types of innate immune response that predispose to long-term inflammatory sequelae. Gene-profiling techniques will also be used to determine why chronic chlamydial infections develop in some individuals and whether antibiotics influence this. Our ultimate aim is to be able to predict which infected individuals are likely to develop long term inflammatory disease and may therefore need more intensive antibiotic therapy or treatments such as therapeutic vaccination.Read moreRead less
The Role Of RasGRP4, A Mast Cell Specific Protein In Mast Cell Growth, Differentiation And Activation
Funder
National Health and Medical Research Council
Funding Amount
$580,433.00
Summary
Mast cells are cells found in the body which are strategically located at mucosal sites and skin where they form a very important barrier in the immune defence. Mast cells have been implicated in a range of inflammatory disorders such as asthma and more recently they have been shown to participate in immunity against bacteria, viruses and fungi. Although a lot of work has been performed to analyze how mast cells respond to different stimuli and what factors are important in their activation, the ....Mast cells are cells found in the body which are strategically located at mucosal sites and skin where they form a very important barrier in the immune defence. Mast cells have been implicated in a range of inflammatory disorders such as asthma and more recently they have been shown to participate in immunity against bacteria, viruses and fungi. Although a lot of work has been performed to analyze how mast cells respond to different stimuli and what factors are important in their activation, there is little work available concerning what in the mast cell controls it's ability to become a mast cell and not any other cell. We have identified a specific protein that has been designated RasGRP4 which is restricted to mast cells and has, we believe, an important role to play not only in guiding immature cells to become mast cells but also in controlling some of the important functions of mast cells. Understanding this molecule more extensively will give us a much better understanding of diseases that the mast cell is involved in such as asthma and other inflammatory disorders. In addition it may shed insights into how mast cells are involved in immunity against bacteria and viruses.Read moreRead less
Biology Of The Novel C-type Lectin Receptor DCL-1 In Innate And Adaptive Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
The innate immune system is the first line of defense in protecting the body from infection. Phagocytic (meaning eating) white blood cells, which include dendritic cells and macrophages are equipped with cell surface proteins These bind the many types of microbes that cause infection, allowing the phagocytes to destroy them (innate immune response). Furthermore, dendritic cells and macrophages have mechanisms to activate additional specific responses (adaptive immune response) mediated by lympho ....The innate immune system is the first line of defense in protecting the body from infection. Phagocytic (meaning eating) white blood cells, which include dendritic cells and macrophages are equipped with cell surface proteins These bind the many types of microbes that cause infection, allowing the phagocytes to destroy them (innate immune response). Furthermore, dendritic cells and macrophages have mechanisms to activate additional specific responses (adaptive immune response) mediated by lymphocytes (T and B cells). We have discovered a cell surface protein, termed DCL-1, which may play a role in uptake of microbes by phagocytes and activation of innate and adaptive immune responses. This project will examine the mechanisms whereby DCL-1 mediates these immune responses. Understanding the mechanism may allow us to exploit DCL-1 for tumor immunotherapy.Read moreRead less
Role Of Plasmacytoid Dendritic Cells And Neutrophils In The Generation Of Antiviral Immunity
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Work described in this application is important in understanding how two very different types of white blood cells, namely neutrophils and plasmacytoid dendritic cells (PDC), contribute to the generation of an effective immune response and control of virus growth. Both these cell types are activated in the earliest phase of the host response and are likely to play crucial roles in determining the nature of the later components of the response. We have recently shown that animals depleted of Gr-1 ....Work described in this application is important in understanding how two very different types of white blood cells, namely neutrophils and plasmacytoid dendritic cells (PDC), contribute to the generation of an effective immune response and control of virus growth. Both these cell types are activated in the earliest phase of the host response and are likely to play crucial roles in determining the nature of the later components of the response. We have recently shown that animals depleted of Gr-1+ cells, with monoclonal antibody (mAb) RB6-8C5, rapidly succumb to a poxvirus infection (mousepox) with 100% mortality. In contrast, mice treated with a control mAb clear the infection very effectively. Host responses essential for recovery from mousepox, including antiviral cytotoxic T lymphocyte (CTL) response and gamma interferon production, are severely diminished in mice treated with the Gr-1+ cell depleting mAb. Since the mAb can potentially deplete both neutrophils and PDC, this raises the important question of whether one or both of these cell types may be involved in the generation of cytokine and cell-mediated immune responses to viral infection. Although PDC and neutrophils themselves are not thought to present antigen to T cells, the elucidation of how they may control the generation of this major arm of the immune response will be novel and has important implications for vaccine design. Virtually nothing is known about how neutrophils or PDC influence viral antigen presentation by antigen presenting cells. Several murine models of viral infection, that in many ways mimic the diseases in humans, will be used to map the sequence of events initiated by PDC and neutrophils and which end in the clearance of virus from the host. Understanding these pathways and identifying the essential mediators and their interactions is critical in elucidating the role of the two cell types in the host response to virus infection.Read moreRead less