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
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
I work on the molecular mechanisms of innate immunity. Priorities of my work are the immune response to pathogens such as viruses and bacteria and to cancer.