Functional Analysis Of The Ym2 Chitinase-like Lectin In Allergic Airways Disease
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
The prevalence of asthma is widespread and nationally affects over two million Australians. Consequently, one of the Country s National Health Priorities is to improve our understanding of this condition. Analyses of the asthmatic lung reveal an airway wall that is thickened, an airway lumen that is obstructed and abnormal spasmogenicity of the airway smooth muscle: processes that collectively contribute to both acute and chronic respiratory dysfunction. Asthmatics develop an immune response tha ....The prevalence of asthma is widespread and nationally affects over two million Australians. Consequently, one of the Country s National Health Priorities is to improve our understanding of this condition. Analyses of the asthmatic lung reveal an airway wall that is thickened, an airway lumen that is obstructed and abnormal spasmogenicity of the airway smooth muscle: processes that collectively contribute to both acute and chronic respiratory dysfunction. Asthmatics develop an immune response that is biased toward production of allergy-related T helper 2 cytokines of which interleukin (IL)-13 is a potent mediator of disease. However, the molecular processes linking IL-13 with abnormal airway wall changes are unclear. To identify previously uncharacterised IL-13-related molecules, we used a protein profiling approach that identified a novel lectin (carbohydrate-binding protein) termed Ym2, which is secreted abundantly into the airway fluid of mice in which allergic airways disease has been induced. Preliminary studies suggest that Ym2 is an intermediary of IL-13 that is involved in respiratory dysfunction. This project aims to work out how Ym2 interacts with the molecules and cells of the respiratory tract to regulate allergic disease. Specific inhibitors of Ym2 will be developed to examine what happens to allergic responses when Ym2 can t function; transgenic mice will be developed to determine if we see features of allergy when Ym2 is over-expressed in the normal lung, and human samples will be screened to identify the human counterpart of Ym2 and whether this counterpart is secreted into the lung fluid of asthmatics. Defining the mechanism by which Ym2 regulates the pathogenesis of allergic disease will not only contribute to our basic understanding of the processes underlying asthma pathology, but also generate new information for better design of therapeutics directed against specific mediators of this debilitating and widespread disease.Read moreRead less
Streptococcus pneumoniae (the pneumococcus) is an important human pathogen, which is responsible for the deaths of millions of children each year in developing countries. The high morbidity and mortality associated with pneumococcal disease is also being exacerbated by the rate at which this organism is acquiring resistance to multiple antibiotics. Existing pneumococcal polysaccharide vaccines are poorly immunogenic in young children and only provide cover against a limited range of serotypes. S ....Streptococcus pneumoniae (the pneumococcus) is an important human pathogen, which is responsible for the deaths of millions of children each year in developing countries. The high morbidity and mortality associated with pneumococcal disease is also being exacerbated by the rate at which this organism is acquiring resistance to multiple antibiotics. Existing pneumococcal polysaccharide vaccines are poorly immunogenic in young children and only provide cover against a limited range of serotypes. Serotype coverage is even lower in the more immunogenic conjugate vaccines currently being developed; these will also be very expensive, thereby limiting their use in developing countries, where the need for effective paediatric vaccines is greatest. Pneumococci produce a variety of proteins which are important in causing disease, but the relative contribution of these factors at each stage of the infection process remain to be determined. Moreover, virtually nothing is known of the mechanism whereby these virulence factors are regulated in response to the external environment of the bacterium. In view of this, we are conducting a comprehensive examination of the mechanisms of pathogenesis of pneumococcal disease, with particular reference to the role of putative virulence proteins. This information is being used to develop cheap and effective vaccines based on pneumococcal protein antigens common to all serotypes.Read moreRead less
Pathogenesis And Prevention Of Shiga Toxigenic Escherichia Coli Infections
Funder
National Health and Medical Research Council
Funding Amount
$341,320.00
Summary
Shiga toxin (Stx)-producing strains of Escherichia coli (STEC) are known to cause diarrhoea and haemorrhagic colitis in humans. In a proportion of cases, this leads to potentially fatal systemic complications, such as haemolytic uraemic syndrome (HUS), which is the commonest cause of acute renal failure in children. HUS has a high mortality rate in spite of intensive supportive therapy. Morbidity is also substantial, as permanent renal damage and neurological sequelae occur in a significant prop ....Shiga toxin (Stx)-producing strains of Escherichia coli (STEC) are known to cause diarrhoea and haemorrhagic colitis in humans. In a proportion of cases, this leads to potentially fatal systemic complications, such as haemolytic uraemic syndrome (HUS), which is the commonest cause of acute renal failure in children. HUS has a high mortality rate in spite of intensive supportive therapy. Morbidity is also substantial, as permanent renal damage and neurological sequelae occur in a significant proportion of survivors. Large outbreaks of STEC infection are becoming increasingly common, and highlight the threat to public health posed by these bacteria. The serious systemic complications of STEC disease, as well as much of the intestinal pathology, are directly attributable to Stx. However, pathogenesis is multifactorial and capacity of the bacteria to colonize the gut is a crucial virulence trait. STEC infections can now be diagnosed very early in the course of disease, but currently no effective therapeutic intervention is possible. We are addressing this deficiency by developing a novel therapy for STEC infections based on a genetically modified harmless bacterium capable of binding toxin in the gut. Vaccines capable of preventing transmission of STEC disease in the community are also needed, but development of these demands a full understanding of the mechanisms whereby diverse STEC strains adhere to intestinal epithelium and colonize the human gut. We are therefore also examining the interaction between STEC and gut epithelial cells at the cellular and molecular level, with a view to identifying and assessing the vaccine potential of key determinants of adherence.Read moreRead less
Exploration Of Exposures Associated With Bedding That Are Risks For Childhood Allergy And Asthma Symptoms
Funder
National Health and Medical Research Council
Funding Amount
$263,500.00
Summary
Asthma prevalence in Australia has doubled in the last 20 years, with 1 in 4 children now affected. House dust mites are probably the single most important allergen associated with asthma. The prevalence of mite allergy is linked to exposure, and such allergy when combined with high exposure, is a potent risk factor for asthma exacerbations. The current international advice for managing mite-allergic asthma, strongly advocates the use of bedding encasings as the best way to reduce exposure. Howe ....Asthma prevalence in Australia has doubled in the last 20 years, with 1 in 4 children now affected. House dust mites are probably the single most important allergen associated with asthma. The prevalence of mite allergy is linked to exposure, and such allergy when combined with high exposure, is a potent risk factor for asthma exacerbations. The current international advice for managing mite-allergic asthma, strongly advocates the use of bedding encasings as the best way to reduce exposure. However, three recent major trials using encasings and a meta-analysis of earlier trials all fail to show a clinical benefit. One of the applicants (ET) recently showed, using expertise in measuring personal exposure, that these encasings, as used, fail to significantly reduce aeroallergen exposure. By contrast, 3 recent Australian studies, involving the applicants, AK, ALP and NG showed that feather bedding compared to synthetic bedding, was strongly protective for asthma - the opposite of public advice. The suggested mechanisms involve reduced exposure to mite allergens, or altered exposure to bacterial endotoxin, but persuasive experimental support is lacking. We also propose a novel hypothesis that feather exposure may induce allergic 'tolerance'. Currently there is a lack of certainty about valid approaches to prevent asthma, and the Global Initiative for Asthma has described the need to understand mechanisms and improve interventions as urgent. This project is an ideal opportunity to combine the expertise of the CIA (ET) in measuring airborne exposures (mite, endotoxin, proteins) with that of the others who have expertise in children's asthma, and who are already involved in two large clinical trails involving different bedding and allergen avoidance. Our measurements of these bedding exposures and their clinical outcomes will provide, for the first time, a quantitative basis to refine public health allergen-based interventions to prevent and manage asthma.Read moreRead less