Genetic Modulation Of The Host Response To Pulmonary TB
Funder
National Health and Medical Research Council
Funding Amount
$540,273.00
Summary
Tuberculosis (TB) is an enormous global health problem. The World Health Organisation estimates that TB, which is caused by infection with the bacteria Mycobacterium tuberculosis, infects 2 billion individuals, leading to 2 million deaths and 8 million new cases of disease per year. Most TB disease is not manifest at the time of infection, but is a reactivation of latent disease in people who do not completely eradicate the primary infection. In a latent infection an effective chronic host respo ....Tuberculosis (TB) is an enormous global health problem. The World Health Organisation estimates that TB, which is caused by infection with the bacteria Mycobacterium tuberculosis, infects 2 billion individuals, leading to 2 million deaths and 8 million new cases of disease per year. Most TB disease is not manifest at the time of infection, but is a reactivation of latent disease in people who do not completely eradicate the primary infection. In a latent infection an effective chronic host response contains dormant TB organisms inside activated macrophages. Cells are recruited to wall off infected macrophages and specific T cells continually induce the activate state with minimal tissue damage (immunopathology). Although currently available antibiotics can kill TB organisms, the treatment is prolonged, expensive, difficult to administer in poorly resourced regions and not effective against multi-drug resistant organisms. New therapies to treat both active disease and prevent reactivation in individuals who are latently infected are urgently required. This proposal will address this problem using a novel approach, namely gene manipulation to augment host immunity to TB and limit concurrent immunopathology. We will construct vectors to increase expression of the key immune molecules, the T lymphocyte activating cytokines IL-12 and IL-23, and the macrophage effector molecules LRG-47 and Indoleamine 2,3-Dioxygenase (IDO). These molecules are known to be involved in TB killing. We will determine if increasing their expression increases the killing capacity of TB-infected macrophages and we will examine how these molecules interact to aid clearance of the TB bacilli. This internationally competitive grant will further our detailed understanding of the complex immune response to TB organisms and lead to the development of novel therapies to treat TB infection and prevent reactivation of latent disease.Read moreRead less
After infection with viruses, parasites and bacteria the protein SerpinB2 becomes very abundant in macrophages, which are white blood cells involved in inflammation. Unfortunately, what this protein is doing is very unclear. We have found that macrophage SerpinB2 dampens the responses of other immune cells. This grant aims to determine how this is achieved and thereby help resolve the role of this protein in a number of diseases such as cancer, lupus, asthma and pre-eclampsia.
This project is based upon the observation that the mammalian immune system can distinguish between its own genetic material (DNA) and the DNA of infectious agents such as bacteria. This has implications for understanding how the immune system copes with infection, and also for design of new therapies and vaccines. Our central aim is to define how the recognition system for foreign DNA works. The cells that respond most vigorously to foreign DNA are large white blood cells called macrophages. We ....This project is based upon the observation that the mammalian immune system can distinguish between its own genetic material (DNA) and the DNA of infectious agents such as bacteria. This has implications for understanding how the immune system copes with infection, and also for design of new therapies and vaccines. Our central aim is to define how the recognition system for foreign DNA works. The cells that respond most vigorously to foreign DNA are large white blood cells called macrophages. We are investigating how a key protein that is required for these responses functions and what genes it turns on. The type of immune responses initiated by foreign DNA may be useful in treatment of allergies and cancer, and for improving vaccinations.Read moreRead less
Macrophage Polarisation And Control Of Pulmonary Inflammation.
Funder
National Health and Medical Research Council
Funding Amount
$895,494.00
Summary
As key immune cells, macrophages are polarised to phenotypes that turn inflammation on or off. In cystic fibrosis, defective macrophage polarisation enhances inflammation and prevents lung repair. We are defining the molecules and cellular pathways that control this process and identifying targets for existing drugs that can be used to reprogram macrophages and restore lung repair to improve patient outcomes.
Unconventional Mechanisms For Activating The NLRP3 Inflammasome
Funder
National Health and Medical Research Council
Funding Amount
$747,031.00
Summary
Many inflammatory driven diseases such as arthritis, atherosclerosis and septic shock are also associated with cell death. This project will identify, at the molecular level, how cell death signalling specifically acts to trigger pathological inflammation. As such, it will identify novel targets for the development of next generation anti-inflammatory drugs.
Exploring And Targeting The Anti-Inflammatory Signalling Mechanisms Of Interleukin 37
Funder
National Health and Medical Research Council
Funding Amount
$1,018,306.00
Summary
Cytokines are messenger proteins that function as master regulators of biological processes; thus they play central roles in many diseases. The rare cytokines that block inflammation do so by dampening the immune system’s potentially destructive force, making them attractive targets for drug development. We showed that interleukin 37 is a powerful anti-inflammatory cytokine, and will now evaluate its mechanisms of action and its efficacy against several severe diseases, including cancer.
I am a cellular immunologist interested in the study of cytokines and other regulatory molecules in inflammatory and immune responses. One key area relates to the effect on sunlight on cell-mediated immunity.