Acid Resistance Mechanisms Of Helicobacter Pylori And Their Impact On Gastric Colonisation
Funder
National Health and Medical Research Council
Funding Amount
$287,036.00
Summary
The gastric bacterium, Helicobacter pylori, infects more than half the population of the globe. H. pylori may cause either no symptomatic disease, induce peptic ulcers or be responsible for one of the major killing cancers, gastric cancer. Millions die or suffer from this infection each year. Yet we are remarkably ignorant of why the infection causes these different patterns of disease. This project aims to provide evidence to show that the very mechanism the bacterium has acquired to help it re ....The gastric bacterium, Helicobacter pylori, infects more than half the population of the globe. H. pylori may cause either no symptomatic disease, induce peptic ulcers or be responsible for one of the major killing cancers, gastric cancer. Millions die or suffer from this infection each year. Yet we are remarkably ignorant of why the infection causes these different patterns of disease. This project aims to provide evidence to show that the very mechanism the bacterium has acquired to help it resist stomach acid and so live in the stomach, is responsible for these differences. I.e. The organism lives in different parts of the stomach due to differences in local acid at that site. If the acid in a particular part of the stomach is too high, the acid resistance mechanism cannot cope. If the acid is too low, the organism also cannot grow well. Because the bacterium has evolved to only thrive in a relatively narrow range of acid, it will behave very differently in these different parts of the stomach. This results in different diseases. Various populations in different countries of the world have different levels of acid production and this also explains why in some countries duodenal ulcers predominate and in others gastric ulcer- gastric cancer is the norm. Showing why H. pylori lives where it lives will provide fundamental information relevant to understanding some of the world s major diseases and will also provides insights relevant to the design of new therapeutic approaches.Read moreRead less
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
Nasopharyngeal Metagenomics In Indigenous Children: Correlations With Otitis Media Aetiology And Treatment Failure.
Funder
National Health and Medical Research Council
Funding Amount
$82,420.00
Summary
Indigenous children experience excessive rates of otitis media. The disease is caused by many different bacteria. Previously, researchers have only been able to examine one bacterium at a time. Metagenomics is a new science which allows study of numerous bacteria simultaneously. Using metagenomic methods, we aim to understand how otitis media develops and why some children do not respond to therapy. This will allow design of better interventions to improve ear health for Indigenous children.
Environmental Regulation Of Virulence In Attaching And Effacing Enterobacteria
Funder
National Health and Medical Research Council
Funding Amount
$569,063.00
Summary
Disease-causing bacteria must respond to the extreme conditions, such as acid and bile, which they encounter in their hosts. They achieve this by sensing their environment and activating genes that enhance their survival and ability to cause disease. In this project we will define the mechanisms by which these sensing and response pathways occur, using E. coli as a model. The information obtained from this research should lead to new strategies to treat and prevent bacterial infections.
Characterisation Of A Newly-discovered, Virulence-associated, Protein Secretion System Of Enteropathogenic E. Coli
Funder
National Health and Medical Research Council
Funding Amount
$582,149.00
Summary
The cell walls of bacteria act as a barrier to the export of any proteins they produce. We recently discovered a protein secretion system, which diarrhoea-causing strains of E. coli require to cause disease. The aim of this study is to characterise this secretory system, and discover how it functions and what it secretes. The knowledge obtained from this research will shed new light on how E. coli causes disease and could reveal novel methods to treat and prevent infections with this bacterium.
Protease-activated Receptor-1 (PAR-1) And Regulation Of Helicobacter Pylori Induced Mucosal Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$478,090.00
Summary
Helicobacter pylori infections cause chronic gastritis which in some people results in stomach cancer or ulcers. We have identified a novel host factor, PAR-1, important for preventing this inflammation. We will use mice to identify how this molecule protects against gastritis and samples from patients to examine its importance in human disease. This will help explain why these diseases develop in some people but not others and perhaps allow identification of those at risk of developing disease.
Novel Compounds For Use As Inhibitors Of Virulence Of Human Pathogens
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
There is growing concern over the emergence of multi-drug resistant strains of bacteria which are no longer treatable with the current generation of antibiotics. This highlights the urgent need for development of the next generation of therapeutic agents to supplement or replace the current antibiotics. Our research team has identified a class of compounds which are naturally produced by a marine alga that may be effective in the control of bacterial pathogens. These compounds work by interferin ....There is growing concern over the emergence of multi-drug resistant strains of bacteria which are no longer treatable with the current generation of antibiotics. This highlights the urgent need for development of the next generation of therapeutic agents to supplement or replace the current antibiotics. Our research team has identified a class of compounds which are naturally produced by a marine alga that may be effective in the control of bacterial pathogens. These compounds work by interfering with the way many pathogens regulate the production of virulence traits. Some bacteria are able to signal members of their population by the specific uptake and recognition, through a receptor protein, of chemical cues they secrete into the environment. Accumulation of these cues or signals triggers expression of the genes that code for the virulence traits. Moreover, one particular class of these signal response proteins has been identified in many pathogens and has been shown to regulate protease production and production of a protective extracellular slime layer called a capsule. If one or more of these traits can be blocked, then the virulence of the bacterium can be reduced. We have preliminary data which demonstrates that the algal compounds do in fact prevent the expression of virulence traits and thus should be useful as new agents for the treatment of disease. The causative agents of cholera and severe gatroenteritis, Vibrio cholerae and V. parahaemolyticus respectively, have one or the other of these virulence traits, but the pathogen Vibrio vulnificus has all three and therefore is an excellent model pathogen. We propose to explore the ability of the algal compounds to specifically shut down expression of virulence factors with a long term aim for the development of these compounds as novel antimicrobial therapies for the post-antibiotic era.Read moreRead less