Improving Immunoassays For The Diagnosis Of Latent Tuberculosis Infection In Children
Funder
National Health and Medical Research Council
Funding Amount
$489,006.00
Summary
WHO highlights the urgent need for new tests for tuberculosis (TB). Diagnosis of latent TB infection (LTBI) is vital in children to prevent them developing active TB. A tuberculin skin test has long been used but is not always accurate. More accurate blood tests (immunoassays) have recently been developed which improve the diagnosis of LTBI in adults. However, we have shown that these assays do not work well in children. We aim to improve the performance of immunoassays for diagnosing LTBI in ch ....WHO highlights the urgent need for new tests for tuberculosis (TB). Diagnosis of latent TB infection (LTBI) is vital in children to prevent them developing active TB. A tuberculin skin test has long been used but is not always accurate. More accurate blood tests (immunoassays) have recently been developed which improve the diagnosis of LTBI in adults. However, we have shown that these assays do not work well in children. We aim to improve the performance of immunoassays for diagnosing LTBI in children.Read moreRead less
Control Of Influenza A Virus Infection By Gamma Interferon-inducible Mediators
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Influenza A virus is a cause of morbidity and mortality worldwide. Due to antigenic shift and drift of the virus, including the emergence of pandemic strains, humans are often challenged with strains different from those to which they have been exposed by vaccination or prior infection. This has historically resulted in very serious increases in illness and death. The most severe pandemic of influenza A virus that has occurred in modern times was the worldwide pandemic of 1918-1920 when over 20 ....Influenza A virus is a cause of morbidity and mortality worldwide. Due to antigenic shift and drift of the virus, including the emergence of pandemic strains, humans are often challenged with strains different from those to which they have been exposed by vaccination or prior infection. This has historically resulted in very serious increases in illness and death. The most severe pandemic of influenza A virus that has occurred in modern times was the worldwide pandemic of 1918-1920 when over 20 million deaths occurred. Development of new interventive strategies to combat virus-related illness therefore remains critical to complement the present vaccine approach. For this, a clear understanding of the host's response to influenza virus infection is essential. For its part, the immune system has at its disposal several strategies to combat influenza A virus. How the immune system deals with the virus is controlled by a complex network of interactions involving cells, cell surface molecules, soluble mediators termed cytokines and chemokines. One cytokine, interferon-gamma, seems to be a key player in the body s ability to get rid of the virus. Here, we are trying to understand how interferon-gamma does this. We believe that this cytokine causes specific immune cells to produce other molecules, such as indolamine 2,3-deoxygenase (IDO) and chemokines, and that it is these molecules that control virus growth. We do not know whether these molecules stop virus growth directly or by creating the right conditions for this. We are interested in understanding the sequence of events that is started by interferon-gamma and ends in the clearance of virus from the lungs. To study the immune response to influenza virus, we use a mouse model that reproduces most features of the human disease. By understanding the events that lead to effective virus clearance in this disease, it may be possible to design new ways in which to combat this problematic infection in humans.Read moreRead less
Role Of Obesity In Impaired Treatment Response In Chronic Hepatitis C: Mechanisms And Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
The overall objective of this Research Project is to examine the mechanisms by which obesity and fatty liver impair the response to antiviral treatment in patients with chronic hepatitis C and to develop specific strategies to monitor and improve the outcome of treatment. In addition, the development of non-invasive strategies and surrogate cell culture systems for the assessment and serial monitoring of the antiviral response will be of substantial benefit.
Role Of PLZF In Regulating The Interferon Response
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state, reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these properties, IFNs have been used clinically against a variety of diseases including viral infections, immunomodulatory disorders and hematologic and solid tumors including renal cel ....The Interferon (IFN) pathway is essential for immune defense against pathogens in vertebrates. IFNs both protect and alert cells about viral, bacterial, and other immune assaults and promote a cellular antiviral state, reduce proliferation, or induce apoptosis depending on the cell type and environment. Based on these properties, IFNs have been used clinically against a variety of diseases including viral infections, immunomodulatory disorders and hematologic and solid tumors including renal cell carcinoma. However, the factors determining outcome of IFN treatment, remain to be determined. We have identified a subset of interferon stimulated genes whose sustained expression was found to correlate with heightened antiviral sensitivity of renal cell carcinoma cell lines to IFN. Many of these genes were found to have binding sites for the transcriptional repressor promyleocytic zinc finger protein (PLZF). PLZF was first identified in a subset of Acute Promyelocytic Leukemia patients and is involved in maintenance of erythroid lineage stem cells and spermatogonial stem cells in male mice. PLZF has not previously been implicated in the IFN response. Accordingly, we investigated the expression of interferon stimulated genes and showed that increased expression of immune related genes depends on PLZF expression. PLZF was also found to directly associate with binding sites in promoters of interferon stimulated genes and that this requires histone deacetylation. Thus, we uncovered a novel function for PLZF in enhancement of IFN associated gene expression. We propose to test the hypothesis that PLZF is an essential component of the IFN response. As a corollary, we will also test whether PLZF expression can be linked to IFN responsiveness in renal cell carcinoma. These studies will establish the role of PLZF in the IFN response and define its utility in predicting IFN responsiveness in therapeutic applications.Read moreRead less
Identification Of Interferon Stimulated Genes That Limit HCV Replication And Predict Therapeutic Outcome
Funder
National Health and Medical Research Council
Funding Amount
$389,224.00
Summary
The only treatment for hepatitis C is Interferon-ribavirin combination therapy. Interferon works by stimulating the liver cells to produce antiviral proteins that can control hepatitis C virus replication, however we do not know which proteins are responsible. The aim of this proposal is to identify those proteins that can limit HCV replication using both a laboratory based and clinical approach and to identify markers that will predict treatment outcome.