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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
Virulence Strategies Of LEE-negative Shiga Toxigenic Escherichia Coli
Funder
National Health and Medical Research Council
Funding Amount
$230,246.00
Summary
Shiga toxigenic Escherichia coli (STEC) are a diverse group of pathogens that cause serious gastrointestinal disease in humans, which can lead to life-threatening complications. This project is aimed at understanding how these bacteria cause disease, and is focused on a subset of STEC strains that are highly virulent and produce a novel cytotoxin. A better understanding of the pathogenic mechanisms of STEC is essential for development of improved therapeutic and preventative strategies.
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
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
Primaquine Radical Cure Of Plasmodium Vivax Malaria: A Risk-benefit Analysis
Funder
National Health and Medical Research Council
Funding Amount
$122,714.00
Summary
Vivax malaria causes significant morbidity with over 100 million clinical cases each year and can cause a relapsing illness and chronic anaemia. The only available radical cure of P. vivax requires administration of primaquine, which can cause severe haemolysis in some patients. Our research aims to determine the risks and benefits of giving primaquine to cure vivax malaria using data from meta-analyses of published clinical trials and individual patient results from large multicentre trials.
Functional Genomic Analysis Of The NKT Cell Control Locus Nkt1 And The Bana3/Babs2 Lupus Susceptibility Locus
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
The major populations of white blood cells responsible for learned immunity are the B cells, which make antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells produce antibody. The T and B cells occasionally attack the body's own tissues, resulting in autoimmune diseases such as lupus, in which antibodies are deposited in the tissues causing inflammation in organs such as the brain, skin and especially the kidneys. Another population of ....The major populations of white blood cells responsible for learned immunity are the B cells, which make antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells produce antibody. The T and B cells occasionally attack the body's own tissues, resulting in autoimmune diseases such as lupus, in which antibodies are deposited in the tissues causing inflammation in organs such as the brain, skin and especially the kidneys. Another population of white blood cells, termed NKT cells, plays an important role in keeping the T and B cells in check, and we have found that these cells are deficient in an inbred mouse strain, NOD mice, which develop lupus after exposure to a particular type of bacteria, called mycobacteria. We have found that one of the major genes conferring susceptibility to lupus in these mice lies in the same genetic region as the major gene controlling NKT cell numbers, raising the possibility that the deficiency in NKT cells in this strain predisposes it to developing lupus. The experiments proposed for this project are divided into two groups. The first group test whether increasing NKT cell numbers by either injecting them, or else transferring genes that allow more to develop naturally, can affect the risk of developing lupus. The second group of experiments examine the potential roles of two specific genes which are in the genetic region of interest, and which we think might control both NKT cell numbers and lupus susceptibility. The approach to be used involves sophisticated techniques of genetic analysis, such as the use of mutant mice which carry genetic mutations near the relevant genes, and congenic mice, which are like NOD mice, but carry in addition to NOD genes, genetic regions from a non-autoimmune strain.Read moreRead less
AUSSPRINT:Australian Study Of The Effects Of Strict Potassium Restriction On Neuropathy In Chronic Kidney Disease.
Funder
National Health and Medical Research Council
Funding Amount
$252,653.00
Summary
Patients with chronic kidney disease, when compared to healthy controls, are weaker, less active and have reduced exercise capacity. These physical limitations have in turn been linked to low quality of life and higher mortality rates. Studies have shown that high blood levels of potassium may cause nerve damage in chronic kidney disease patients.This study explores the benefits of strict potassium restriction as a means of reducing neuropathy rates in patients with chronic kidney disease.