Cells of the immune system need to recognise characteristic viral and bacterial molecules, in order to identify infection. Some immune cells can detect the presence of viral and bacterial DNA. The cells respond by making a number of anti-viral or anti-bacterial molecules, as well as activating other cells to fight the infection. The effect of bacterial DNA can be mimicked by certain short synthetic pieces of DNA. The potent activity of this synthetic DNA (termed CpG DNA ) is being exploited in a ....Cells of the immune system need to recognise characteristic viral and bacterial molecules, in order to identify infection. Some immune cells can detect the presence of viral and bacterial DNA. The cells respond by making a number of anti-viral or anti-bacterial molecules, as well as activating other cells to fight the infection. The effect of bacterial DNA can be mimicked by certain short synthetic pieces of DNA. The potent activity of this synthetic DNA (termed CpG DNA ) is being exploited in a number of clinical trials for treatment of cancer and allergy, as well as to improve vaccinations. Despite the rapid advance towards clinical application, there is still much basic information to learn about how CpG DNA acts on cells. The molecule to which DNA binds in order to activate the cells is called TLR9. TLR9 is not on the surface of cells, but within cells. In a bacterial infection, cells called macrophages engulf and digest bacteria and release the bacterial DNA within the cell, where it binds to TLR9. In other cases, including when CpG DNA is used therapeutically, the DNA needs to be taken up into the cell. Evidence shows that there is a receptor on the cell surface which binds DNA, and takes it into the cell. In this project we propose to identify this DNA uptake receptor. Apart from the use of CpG DNA, there are a number of other proposals for the therapeutic use of DNA. Although it is known that DNA enters into cells, the route for this has not been established. Whilst CpG DNA can activate immune cells, some other distinct DNA molecules can prevent the activation. We will examine whether these inhibitory DNA molecules bind more effectively to TLR9 than the CpG DNA, but do not activate the cell. These inhibitory molecules are proposed as a therapy for the autoimmune disease lupus, which involves inappropriate responses to DNA, and is thought to involve TLR9. In order to develop therapies, a detailed knowledge of how they work is essential.Read moreRead less
Interferon Regulatory Factor 6: A Novel Epithelial-specific Regulator Of Mucosal Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$517,989.00
Summary
Epithelial cells lining the respiratory and gastrointestinal tracts play pivotal roles in protecting us from infection. Inflammatory factors released by epithelial cells are important for fighting infection; however, they also contribute to chronic inflammatory diseases. We aim to understand how a protein called IRF6 regulates the inflammatory response of epithelial cells. The knowledge gained will identify new therapeutic approaches for inflammatory diseases.
Pattern Recognition Receptors In Inflammation And Infection
Funder
National Health and Medical Research Council
Funding Amount
$622,655.00
Summary
Innate immunity provides our first line of defence against infections, but pathogens can overcome this system. Understanding how microbes disable innate immunity can teach us how to prevent and/or treat infectious diseases. Innate immunity acts by initiating inflammation. Many important acute and chronic diseases develop when this process is dysregulated. Blocking innate immunity thus has potential to treat many diseases. This project aims to understand innate immunity in these contexts.
Reprogramming Innate Immunity To Combat Inflammatory And Infectious Diseases
Funder
National Health and Medical Research Council
Funding Amount
$1,788,220.00
Summary
Our immune system protects us from infection, but also drives cancer, autoimmune diseases, inflammatory diseases and many other conditions. Innate immunity, a key component of our immune system, mediates the pathology that is associated with these diseases. This research program aims to define innate immune mechanisms that combat infection and/or drive inflammation-mediated diseases. It also aims to deliver novel anti-infective and anti-inflammatory strategies.
Neuronal Toll-like 2 Receptors Contribute To The Spread Of Parkinson's Disease
Funder
National Health and Medical Research Council
Funding Amount
$900,010.00
Summary
How the pathological protein in Parkinson’s disease (PD), ?-synuclein, spreads through the brain remains unknown. Toll-like receptor 2 (TLR2) located on microglial cells have been identified as the receptor responsible for the internalization of ?-synuclein by this cell. We have found TLR2 in PD neurons accumulating Lewy pathologies, suggesting that neuronal TLR2 contributes to the neuronal spread of ?-synuclein in PD, a theory requiring further biological evidence prior to therapeutic targeting
The Role Of Toll Like Receptors In Leukocyte Activation And Adherence In Glomeruli In Auto-immune Glomerulonephritis
Funder
National Health and Medical Research Council
Funding Amount
$82,554.00
Summary
1 in 7 Australians have Kidney disease. Kidney disease tends to be progressive and over 8500 Australians require renal replacement therapy (dialysis). The cost of dialysis from 2004-2010 in Australia will be $ 4.5 billion. Auto-immune disease and Diabetes accounts for nearly 60% of kidney failure. Whilst current regimes exist to treat Kidney disease these are limited because they are deleterious side-effects. Improved understanding of the mechanism of disease will lead to improved treatments.