Genetic Adaptations Of Mycobacterium Tuberculosis For Intracellular Survival
Funder
National Health and Medical Research Council
Funding Amount
$187,677.00
Summary
Tuberculosis (TB) remains a significant global public health problem and new approaches to its treatment and prevention are urgently needed. The disease is caused by infection with Mycobacterium tuberculosis, a slow growing organism that lives within cells. How it adapts to survive in this intracellular environment is unknown. Recently the complete genome of M. tuberculosis was sequenced and new techniques developed for manipulating its genes. We plan to use these techniques to identify genes th ....Tuberculosis (TB) remains a significant global public health problem and new approaches to its treatment and prevention are urgently needed. The disease is caused by infection with Mycobacterium tuberculosis, a slow growing organism that lives within cells. How it adapts to survive in this intracellular environment is unknown. Recently the complete genome of M. tuberculosis was sequenced and new techniques developed for manipulating its genes. We plan to use these techniques to identify genes that are more active within the cells. Genes are controlled by short sequences of preceding DNA called promoters. If these promoters are randomly placed in front of readily identifiable reporter genes and inserted into a suitable host strain, it is possible to select for those promoters expressed only inside cells and then identify the promoter and its gene by sequence analysis. We plan to use two types of reporter genes. First, we shall place the M. tuberculosis DNA containing promoters before the gene for a naturally fluorescent protein within the M. bovis BCG host strain and then infect macrophages. If the promoters are switched on inside the cell, the macrophages will become green and can be selected and the promoter identified. After several rounds of selection the promoter is isolated and identified. Second, we shall select the promoters by their ability to produce a protein that is on the surface of the bacterium. We will use these intracellular genes to make better vaccines against TB. Genes that enhance intracellular survival may contribute to the virulence of the TB organism. By removing these genes we can make an attenuated organism suitable as a vaccine. We will test for reduced virulence by growth inside cells in mice. We will also use the intracellular promoter to improve the current BCG vaccine. Proteins expressed inside the cell may also be targets for new TB drugs.Read moreRead less
Identification Of Type III Effectors In Salmonella
Funder
National Health and Medical Research Council
Funding Amount
$555,325.00
Summary
Salmonella is a major cause of disease across the world. In order to cause disease, Salmonella injects certain molecules into our own human cells to reprogramme them to promote Salmonella infection. This work aims to identify a large proportion of those molecules injected by Salmonella. Once identified, a more complete understanding of exactly how Salmonella reprogrammes our cells will be possible, enabling new avenues for therapeutics.
Global Regulatory Networks That Control Virulence In Clostridium Perfringens
Funder
National Health and Medical Research Council
Funding Amount
$531,557.00
Summary
This research focuses on the bacterium that is responsible for clostridial myonecrosis, or gas gangrene, an often fatal human infection. The objective is to determine how this bacterium controls the production of the various factors that are required to cause disease. The aims will be achieved by the integrated application of the latest techniques in microbiology and molecular biology and will result in a significant advancement in our knowledge of this complex regulatory process.
Regulation Of Virulence Gene Expression In Clostridium Perfringens
Funder
National Health and Medical Research Council
Funding Amount
$585,497.00
Summary
This project involves the analysis of a bacterium that causes gas gangrene. We have shown that a previously unknown regulatory protein modulates the ability of this bacterium to cause disease. We aim to determine what turns on the protein's activity, how it controls the factors that contribute towards disease and what specific factors are involved in disease. The major outcome will be a better understanding of the mechanisms of virulence gene regulation, which will lead to improved methods of di ....This project involves the analysis of a bacterium that causes gas gangrene. We have shown that a previously unknown regulatory protein modulates the ability of this bacterium to cause disease. We aim to determine what turns on the protein's activity, how it controls the factors that contribute towards disease and what specific factors are involved in disease. The major outcome will be a better understanding of the mechanisms of virulence gene regulation, which will lead to improved methods of disease control.Read moreRead less
Characterisation Of A Novel Porphyromonas Gingivalis Regulatory Protein That Controls Virulence Related Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$569,620.00
Summary
In this study we will characterise the manner in which genes essential for the virulence of Porphyromonas gingivalis, a bacterium associated with chronic periodontitis, are regulated. This will provide information on how this bacterium causes disease and may offer opportunities for the development of new treatment strategies.
Regulatory Networks Controlling Virulence In Neisseria Gonorrhoeae And Neisseria Meningitidis.
Funder
National Health and Medical Research Council
Funding Amount
$147,500.00
Summary
Bacteria that cause disease produce substances called virulence determinants, often on their cell surface. These virulence determinants are either directly involved in allowing infection to take place, or cause the damage that we recognize as an infectious disease. Some virulence determinants are produced all the time, while others are only made under particular conditions, that is, their expression is regulated. To target efforts in the development of new vaccines and treatments, it is importan ....Bacteria that cause disease produce substances called virulence determinants, often on their cell surface. These virulence determinants are either directly involved in allowing infection to take place, or cause the damage that we recognize as an infectious disease. Some virulence determinants are produced all the time, while others are only made under particular conditions, that is, their expression is regulated. To target efforts in the development of new vaccines and treatments, it is important to identify all the virulence determinants produced by a particular bacterial species, but also to know which are regulated, and the environmental signals that determine their expression. Neisseria gonorrhoeae and Neisseria meningitidis are two important disease-causing bacteria that exclusively infect humans and cause gonorrhoea, and meningitis. The complete DNA sequence of both of these bacteria is now known. From computer analysis of these data, it appears that these bacteria have few of the specific regulatory systems that are present in other bacteria. Because of the limited repertoire of regulatory systems still present in N. gonorrhoeae and N. meningitidis, it is feasible to mutate each one and determine which are involved in regulation of virulence determinants. We have made copies of every individual gene found in the DNA sequence of these bacteria and have attached each one individually to a glass slide to form a microarray measuring 18mm x 18mm. This microarray will allow us to monitor the expression of every gene in these bacteria in response to environmental signals. This information will be used to identify all the virulence genes controlled by each regulatory system. Such an analysis has never been previously achieved for any bacterial species, because of the number and complexity of the regulatory systems usually present.Read moreRead less
Non-coding RNA Regulation Of Virulence In Enterohaemorrhagic E. Coli
Funder
National Health and Medical Research Council
Funding Amount
$389,313.00
Summary
Shiga toxins cause potentially fatal haemolytic uremic syndrome (HUS) and are transferred between bacterial pathogens by bacteriophage (bacterial viruses). We have recently found that the Shiga toxin encoding bacteriophage encodes an unusually large number of non-coding RNAs (RNA regulators of gene expression). This Project aims to understand how these RNA regulators benefit the Shiga toxin bacteriophage and use this knowledge to develop interventions that will prevent expression of the toxin.