Role Of Regulatory Genes In The Gastrointestinal Pathogen, Clostridium Difficile
Funder
National Health and Medical Research Council
Funding Amount
$287,036.00
Summary
When patients are treated in hospital with antibiotics they sometimes develop chronic diarrhoea or colitis syndromes that are very difficult and expensive to treat. This project involves the analysis of the bacterium that generally causes these gastrointestinal diseases. We know that this microorganism is present in the hospital environment and that it produces potent protein toxins that are responsible for these diseases but we know little about the actual disease process. In most bacteria that ....When patients are treated in hospital with antibiotics they sometimes develop chronic diarrhoea or colitis syndromes that are very difficult and expensive to treat. This project involves the analysis of the bacterium that generally causes these gastrointestinal diseases. We know that this microorganism is present in the hospital environment and that it produces potent protein toxins that are responsible for these diseases but we know little about the actual disease process. In most bacteria that cause disease there are regulatory networks that control the expression of the genes responsible for the disease process. In this project, we aim to develop an understanding of how these regulatory networks operate in this particular bacterium. The latest techniques of molecular biology will be used to investigate several specific regulatory genes at the functional level. Since the entire DNA sequence of this bacterium is now known we will also use a broader research approach that makes use of this knowledge to examine all of potential regulatory networks that exist in this bacterium. Finally, we will develop new methods for the genetic analysis of the causative bacterium so that we will be better able to elucidate the role of specific genes in the disease process. By understanding how this bacterium controls the production of the proteins that interact with human intestinal cells to cause disease we hope to be able to prevent such diseases from occurring. The successful completion of the project therefore will make a major contribution to the development of improved methods for the control and treatment of these chromic diarrhoea and colitis syndromes.Read moreRead less
Antibiotic resistance increases mortality and costs in the Intensive Care Unit (ICU), but the impact of antibiotic therapy has not been adequately studied. We propose to characterise the behaviour of key elements of the bacterial microflora (resistant bacteria and major resistance genes) in response to antibiotics. We have developed new rapid diagnostics to harness these data and this proposal has the potential to greatly improve diagnostic speed and accuracy and thus clinical outcomes.
The rapid emergence and spread of antibiotic resistance in bacteria that cause infectious diseases is of major concern to public health authorities throughout the world. Many of the genes that are responsible for this resistance are carried on mobile genetic elements, which are discrete segments of genetic material that can move from one bacterium to another. These genetic elements are important vehicles for the transmission of virulence and antibiotic resistance genes in most bacteria. This pro ....The rapid emergence and spread of antibiotic resistance in bacteria that cause infectious diseases is of major concern to public health authorities throughout the world. Many of the genes that are responsible for this resistance are carried on mobile genetic elements, which are discrete segments of genetic material that can move from one bacterium to another. These genetic elements are important vehicles for the transmission of virulence and antibiotic resistance genes in most bacteria. This project is centred on bacteria that cause intestinal diseases and have the potential to transfer genetic information to other bacteria that are present in the intestine. The focus will be on elucidating the mechanism of action of an enzyme encoded by two of these genetic elements. This enzyme is responsible for the movement of these elements from one site in the bacterial genome to another, by a process that is being increasingly recognised as important in antibiotic-resistant disease-causing bacteria. The project will employ the latest tools of molecular biology to determine the function of this enzyme, and its associated genetic elements, at the detailed molecular level. These studies will contribute to our understanding of how these antibiotic resistance elements are transferred within and between different bacterial cells. In the longer term the project will contribute towards the development of improved methods for the control and treatment of infectious diseases.Read moreRead less
Characterisation Of Enterohaemorrhagic Escherichia Coli Lacking Classical Virulence Markers
Funder
National Health and Medical Research Council
Funding Amount
$140,660.00
Summary
Some intestinal infections with the intestinal bacterium, E. coli, can result in severe, often fatal, kidney disease called the haemolytic uraemic syndrome. It is important for the diagnosis and treatment of this condition that the infections are detected swiftly. Current means of identifying this virulent form of E. coli are inadequate and do not account for all types of the bacteria that can cause severe disease. Children are particularly susceptible to life threatening infections with this ty ....Some intestinal infections with the intestinal bacterium, E. coli, can result in severe, often fatal, kidney disease called the haemolytic uraemic syndrome. It is important for the diagnosis and treatment of this condition that the infections are detected swiftly. Current means of identifying this virulent form of E. coli are inadequate and do not account for all types of the bacteria that can cause severe disease. Children are particularly susceptible to life threatening infections with this type of E.coli and usually acquire the infection by consuming contaminated food or water. This organism is currently a global food safety problem and the bacteria are especially prevalent in ground beef products and water or vegetables that have been contaminated with cattle faeces. In this study we aim to identify new bacterial genes and proteins that may be used to improve current means of detecting and diagnosing this kind of E.coli. A great deal is known about the way in which the classical strains of this virulent E .coli colonise the intestine however a small but significant group of these organisms do not carry known colonisation factors. We aim to identify bacterial proteins in these non-classical strains of E.coli which are needed for attachment of the bacteria to the host. Identifying how these bacteria interact with the host may help us to develop improved means of detecting and diagnosing this life-threatening infection.Read moreRead less
Genetics And Biochemistry Of Biosynthesis Of The Cell Wall Of Mycobacteria
Funder
National Health and Medical Research Council
Funding Amount
$260,831.00
Summary
Mycobacteria commolnly cause human disease. The major killer in the group is Mycobacterium tuberculosis which annually causes millions of deaths from tuberculosis (TB) worldwide. Another pathogen from this group is Mycobacterium avium which often infects immunosuppressed people such as those with advanced HIV-AIDS. Mycobacteria have evolved a specialised wall that surrounds their cells which protects them from chemical attack from antibiotics and helps them to establish infections. The major ant ....Mycobacteria commolnly cause human disease. The major killer in the group is Mycobacterium tuberculosis which annually causes millions of deaths from tuberculosis (TB) worldwide. Another pathogen from this group is Mycobacterium avium which often infects immunosuppressed people such as those with advanced HIV-AIDS. Mycobacteria have evolved a specialised wall that surrounds their cells which protects them from chemical attack from antibiotics and helps them to establish infections. The major antibiotic used for TB stops cells from synthesising the protective layer thereby making them very vulnerable to human immune defences. Unfortunately, resistance to this antibiotic is common and new antibiotics are needed to treat mycobacterial infections. We are studying how mycobacteria make the cell wall and are looking for key steps where new drugs might be able to inhibit the process. Our approach is to inactivate genes in the mycobacteria that make the enzymes which control cell wall synthesis. The gene inactivation results in crippled mycobacteria that are unable to make proper cell walls. We analyse the cell wall changes that gene inactivation cause studying the chemical composition of the cell. This helps to identify the steps in cell wall biosynthesis and each step becomes a potential target for new drugs. Each of the weaken mycobacteria can be tested to see how well they can resist antibiotics and to see if they can survive host defences. In this way we can identify which components of the cell wall are critical for them to establish infections and resist antibiotic treatments. Enzymes that participate in the synthesis of such components are prime targets for us to concentrate on to design new antibiotics.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
Examination Of The Role Of Biofilms In Infection With Enteropathogenic Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$456,382.00
Summary
Many infections are caused by bacteria living in communities, known as biofilms. Enteropathogenic E. coli (EPEC) is a major cause of diarrhoea and results in the death of millions of children annually. We have found a link between biofilm formation by EPEC and disease. In this project we will examine how biofilm formation by EPEC occurs and the contribution of biofilm formation to disease. The results of this study may indicate new ways to treat and prevent E. coli diarrhoea.
Identification And Characterisation Of Novel Virulence Genes In Attaching And Effacing Strains Of Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$281,320.00
Summary
Some varieties of Escherichia (E.) coli are harmless bacteria that live in the healthy intestinal tract, whereas others can cause diarrhoea. Those varieties of E. coli which cause diarrhoea include so-called enteropathogenic E. coli (EPEC), which is a leading cause of life- diarrhoea in infants and young children in less developed countries, and enterohaemorrhagic E. coli (EHEC) the cause of hamburger disease. These bacteria are able to cause disease because they possess specific genetic informa ....Some varieties of Escherichia (E.) coli are harmless bacteria that live in the healthy intestinal tract, whereas others can cause diarrhoea. Those varieties of E. coli which cause diarrhoea include so-called enteropathogenic E. coli (EPEC), which is a leading cause of life- diarrhoea in infants and young children in less developed countries, and enterohaemorrhagic E. coli (EHEC) the cause of hamburger disease. These bacteria are able to cause disease because they possess specific genetic information that is absent from harmless varieties of E. coli. Although many of these disease-associated genes have been identified, the specific role of many of them is not known. In addition, it seems likely that many more genes of this type remain to be discovered. The fact that EPEC is host specific means that the mechanisms by which these bacteria cause disease can only be investigated in humans. This is extremely limiting for the number and type of investigations that can be performed. However, there are rabbit-specific strains of EPEC which cause a disease in rabbits that is indistinguishable from that caused by EPEC in children. The aims of this study are to use the rabbit model of diarrhoea to learn more about the contribution of certain specific factors of EPEC to disease causation and to discover new factors of this type. This will be achieved by three complementary strategies: (1) investigating rabbit E. coli for virulence genes and determining if they are present in human strains; (2) examining the effect of inactivating these genes on the ability of E. coli to cause diarrhoea in rabbits; and (3) infecting rabbits with pools of mutant E. coli strains to identify factors that the bacteria require to survive in rabbits. The results of these studies will improve understanding of the mechanisms by which E. coli cause disease and may provide opportunities for the development of novel tools to diagnose, treat and prevent E. coli-associated diarrhoea.Read moreRead less
Investigation Of The Association Between Chlamydial Infection And Asthma In Different Age Groups
Funder
National Health and Medical Research Council
Funding Amount
$382,117.00
Summary
Asthma is a common and severe lung disease that results from inflammation due to allergy and has symptoms of breathing difficulties, wheezing, chest tightness, and cough. Asthma is clinically characterised by the presence of certain types of responses from the immune system. We are looking for ways of preventing and curing asthma. There is a well known link between certain types of bacteria, called Chlamydia, and asthma but it is not known whether people develop asthma first and then get chlamyd ....Asthma is a common and severe lung disease that results from inflammation due to allergy and has symptoms of breathing difficulties, wheezing, chest tightness, and cough. Asthma is clinically characterised by the presence of certain types of responses from the immune system. We are looking for ways of preventing and curing asthma. There is a well known link between certain types of bacteria, called Chlamydia, and asthma but it is not known whether people develop asthma first and then get chlamydial infection or are infected first and this leads to asthma. We have shown that if adult mice are exposed to an allergen during chlamydial infection then the asthma gets worse. However, if newborn mice have a chlamydial infection then asthma is prevented when they are adults. These are preliminary observations, which we need to expand and understand the immune mechanisms that result in infection and allergy so that we can target them with antibiotics or vaccines. We will investigate how the timing of chlamydial infection relative to exposure to allergens (before, during or after) affects the development of asthma in adult mice. Newborns and young children have different immune systems to adults, so we will investigate what effects the infection of young mice has on infection and allergy later in life. We will also test a new vaccine we have developed against chlamydial infection to see if it can prevent chlamydial infection and infection-induced asthma. We will then examine if there is the same association between chlamydial infection and asthma in human asthmatics that present to hospital with exacerbation of their asthma. This work will help us develop new strategies for preventing and curing asthma, which may vary in different age groups. We will identify whether prevention of chlamydial infection by vaccination (or antibiotics) can be used to prevent and treat asthma.Read moreRead less
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.