Contribution Of Shigella And Escherichia Coli Pathogenicity Islands To Diarrhoeal Disease
Funder
National Health and Medical Research Council
Funding Amount
$303,677.00
Summary
Diarrhoea resulting from infection with Shigella and Escherichia coli is a major cause of sickness and death in the developing world, especially in children. Even in Australia, these bacteria, which may be food borne, are occasionally responsible for life threatening infections. In this study, we will investigate the contribution to diarrhoeal disease of large fragments of foreign DNA which have been recently acquired by these bacteria. We will characterise several of these elements in detail, i ....Diarrhoea resulting from infection with Shigella and Escherichia coli is a major cause of sickness and death in the developing world, especially in children. Even in Australia, these bacteria, which may be food borne, are occasionally responsible for life threatening infections. In this study, we will investigate the contribution to diarrhoeal disease of large fragments of foreign DNA which have been recently acquired by these bacteria. We will characterise several of these elements in detail, identifying novel virulence determinants and toxins in the process. We will also explore the means by which these packages of nasty DNA transfer between bacteria and investigate their potential to give rise to new, more virulent strains of bacteria. This study is particularly significant because it will lead to an improved understanding of how bacteria cause disease and may help to guide us in developing better strategies for the prevention of bacterial diarrhoea. Specifically, the work done on characterising large clusters of virulence genes will allow us to construct safer bacterial vaccines and we expect that in the future this knowledge will contribute to the development of new and better diagnostic and therapeutic agents against these harmful bacteria.Read moreRead less
Understanding The Immune Mechanisms Leading To Resolution Of Peanut Allergy
Funder
National Health and Medical Research Council
Funding Amount
$602,472.00
Summary
Food allergy affects up to 10% of children and rates are rising. The greatest rise has been in peanut allergy which is the commonest cause of life threatening reactions. Currently, there is no cure for food allergy. Management relies on food avoidance which is impossible to achieve. Recent deaths in children from food allergy highlight the need for an effective treatment. This project will examine what happens when you grow out of peanut allergy. New information will lead to possible cures.
Investigating Molecular Mechanisms To Better Understand The Recent Rise In Food Allergy Prevalence In Australian Children
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
The prevalence of food allergies in Australia and abroad has risen drastically posing a major preventable public health burden. Further basic research is required and this program aims to make a substantial contribution towards understanding the underlying mechanisms of pediatric food allergy.
Food allergies have emerged as a major public health concern affecting 1 in 10 Australian infants. Hospitals waiting times are in excess of 12-months for specialist services. Recent changes in the environment are driving up rates of food allergy but the mechanisms are unclear. Epigenetics is the science of how the environment influences gene behaviour. This fellowship will address the important and urgent question of how modern environments are changing our genes, leading to food allergy.
Recombinant Bacteria Expressing Oligosaccharide Receptor Mimics For Prevention Of Enteric Infections
Funder
National Health and Medical Research Council
Funding Amount
$451,056.00
Summary
Gastrointestinal infectious diseases kill more than 3 million people each year. The principal microbial pathogens responsible for these infections are known to exploit oligosaccharides on the surface of host cells as receptors for ahesins or toxins. We have developed (and patented) a novel anti-infective strategy, based on mimicry of oligosaccharide receptors for toxins and adhesins produced by enteric pathogens on the surface of harmless carrier bacteria. Oral administration of such recombinant ....Gastrointestinal infectious diseases kill more than 3 million people each year. The principal microbial pathogens responsible for these infections are known to exploit oligosaccharides on the surface of host cells as receptors for ahesins or toxins. We have developed (and patented) a novel anti-infective strategy, based on mimicry of oligosaccharide receptors for toxins and adhesins produced by enteric pathogens on the surface of harmless carrier bacteria. Oral administration of such recombinant probiotics has the potential to prevent enteric infections by binding and neutralizing toxins in the gut lumen and by blocking adherence of the pathogen to intestinal epithelial cells. As a prototypic example, we have developed a bacterium capable of preventing the serious consequences of Shiga toxigenic Escherichia coli (STEC) infections; this agent binds Shiga toxin with very high efficiency and is 100% protective in animal models. The strategy has very broad applications, however, and receptors for virtually any pathogen can be mimicked by expression of appropriate glycosyl transferases in a suitable harmless host bacterium. This proposal involves extension of our existing work to develop therapeutic agents for other important life threatening diarrhoeal diseases including cholera, travellers' diarrhoea, dysentery, antibiotic-associated colitis, rotavirus, etc.Read moreRead less
Structural And Functional Studies On Leptospiral Antigens Central To Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$287,321.00
Summary
Leptospirosis, also known as Weil's disease and canefield fever, is a potentially fatal disease caused by infection with the bacteria Leptospira. Leptospira is able to infect a broad range of animals including livestock and humans. Human infection typically occurs through contact with water or vegetation that has been exposed to the urine of an infected animal. This project focuses on a key step in the bacterial infection in trying to understand how these bacteria adhere to human cells.
Analysis And Regulation Of Leptospiral Virulence Factors.
Funder
National Health and Medical Research Council
Funding Amount
$630,465.00
Summary
Leptospirosis is a globally important infectious disease caused by Leptospira spp. This project aims to identify and characterise factors which play a role in disease development by knocking out genes, then investigating the impact on overall gene-protein expression in the mutant strain and its ability to cause disease. This will allow us to gain insights on mechanisms by which Leptospira spp. cause disease, leading to development of better methods of disease control and prevention.
Dissemination And Virulence Properties Of The She Pathogenicity Island Of Shigella Flexneri.
Funder
National Health and Medical Research Council
Funding Amount
$110,625.00
Summary
Bacterial species belonging to the genus Shigella are responsible for intestinal diseases ranging from mild diarrhoea to life threatening bacillary dysentery. Such diseases kill over a million people, mainly infants in developing countries, every year and lead to serious morbidity and mortality even in industrialised countries with well developed health care systems. In many cases the virulence of Shigella species is augmented by large fragments of DNA, called pathogenicity islands, that carry g ....Bacterial species belonging to the genus Shigella are responsible for intestinal diseases ranging from mild diarrhoea to life threatening bacillary dysentery. Such diseases kill over a million people, mainly infants in developing countries, every year and lead to serious morbidity and mortality even in industrialised countries with well developed health care systems. In many cases the virulence of Shigella species is augmented by large fragments of DNA, called pathogenicity islands, that carry genes which contribute to the development of disease (pathogenesis) in humans. Pathogenicity islands are important genetic elements which appear to spread independantly throughout bacterial populations and therefore contribute to the emergence of new virulence traits in bacteria. Recently, we identified two related pathogenicity islands carried by both Shigella flexneri and other species of the genus Shigella. The two pathogenicity islands belong to a unique class of genetic elements found in Shigella species and virulent strains of the intestinal bacterium E. coli. Our current study is aimed at (1) understanding the mechanisms by which one of these islands, the she pathogenicity island, spreads from one bacterial strain to another to introduce disease-producing or virulence genes to new bacteria and (2) to study how the sigA virulence gene, carried on the she pathogenicity island, contributes to disease development in humans. We know that sigA encodes a protein toxin which contributes to the loss of fluid from the intestines of rabbits that have been experimentally infected with Shigella flexneri. We propose to study the structure and function of the SigA protein to determine how it interacts with tissues to produce a pathological state. Such studies will enhance our understanding of the process of disease development and contribute to the investigation and assessment of new strategies for therapeutic intervention.Read moreRead less
Outer Membrane Proteins Of Leptospira; Role In Immunity And Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$88,500.00
Summary
Leptospirosis is a significant cause of death in tropical regions of the world. Recent outbreaks in Nicaragua and Brazil are timely reminders of the seriousness of disease caused by the Leptospira bacteria. In these outbreaks >10% of people developing the disease did not recover. Spread of the disease does not occur from person to person, but rather from animal to human. Leptospira are shed from infected animals via the urine; human infection may occur through contact with infected urine or u ....Leptospirosis is a significant cause of death in tropical regions of the world. Recent outbreaks in Nicaragua and Brazil are timely reminders of the seriousness of disease caused by the Leptospira bacteria. In these outbreaks >10% of people developing the disease did not recover. Spread of the disease does not occur from person to person, but rather from animal to human. Leptospira are shed from infected animals via the urine; human infection may occur through contact with infected urine or urine contaminated materials. In Australia, leptospirosis is an occupational hazard with dairy farmers, pig handlers, banana pickers and abattoir workers being those most at risk. A recent and alarming development is the emergence of new risk groups associated with certain leisure activities. For example, in the USA three triathletes died from leptospirosis and it was subsequently determined that the source of infection was contaminated swimming water. This project will investigate aspects of the development of disease and immunity during infection by Leptospira. This will be achieved by analysing the set of proteins located on the surface of the bacterium. These proteins play a key role in the development of disease. Using state of the art technology, each of the proteins will be purified and identified. This will enable experiments that will enhance our understanding of the development of disease at a molecular level.Read moreRead less
KILLING OF MYCOBACTERIUM TUBERCULOSIS IN MACROPHAGES VIA THE P2X7 RECEPTOR
Funder
National Health and Medical Research Council
Funding Amount
$226,320.00
Summary
Tuberculosis remains an enormous global health problem. Some 32% of the world population are infected, with over 1 million persons dying each year. The risk of an infected individual developing clinical disease ranges from 2-23% for their lifetime. We know that both environmental factors, such as declining socio-economic conditions, and genetic risk factors such as HLA type contribute to the likelihood of an individual developing disease, but current known factors are insufficient to fully accou ....Tuberculosis remains an enormous global health problem. Some 32% of the world population are infected, with over 1 million persons dying each year. The risk of an infected individual developing clinical disease ranges from 2-23% for their lifetime. We know that both environmental factors, such as declining socio-economic conditions, and genetic risk factors such as HLA type contribute to the likelihood of an individual developing disease, but current known factors are insufficient to fully account for the risk attributed to genetics. The aim of this project is to investigate another potential risk factor involved in the development of tuberculosis, that of P2X7 receptor function. A natural compound, ATP, when added to macrophages is able to kill tuberculosis organisms residing within the macrophage. This process occurs when ATP activates the P2X7 receptor. We have recently identified a mutation in the P2X7 receptor, which causes a loss of receptor function. Individuals who have this mutation are unable to respond to ATP and hence may be unable to kill tuberculosis. Our studies will determine if the mutation we have identified in the P2X7 receptor prevents or inhibits ATP mediated killing of mycobacteria. Furthermore we will determine the frequency of this mutation in TB patients and the general population to determine if this mutation in the P2X7 receptor is a risk factor for the development of tuberculosis disease.Read moreRead less