Regulatory Networks Controlling Virulence In Neisseria Gonorrhoeae And Neisseria Meningitidis.
Funder
National Health and Medical Research Council
Funding Amount
$300,773.00
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 in particular conditions - their expression is regulated. To target efforts in the development of new vaccines and treatments, it is important to identi ....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 in particular conditions - 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. It can be just as important to know whether a virulence determinant is constantly expressed, and therefore represents an invariant target. 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 currently being determined. From computer analysis of these data, it appears that these bacteria have few of the specific regulatory systems that are present in other bacteria. The availability of DNA sequencing data enables an alternative and much more systematic approach to the identification and study of the regulation of virulence determinants. Because of the limited repertoire of regulatory systems still present in N. gonorrhoeae and N. meningitidis, it is feasible to mutate each and determine which are involved in regulation of virulence determinants. We will also be able to identify genes regulated by each system, determine how regulation is achieved, and use this information to identify any presently unknown virulence genes controlled by the same 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
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
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 The Key Role Played By The Persistent Phase Of Chlamydia Pneumoniae In Disease Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$286,320.00
Summary
Chlamydia pneumoniae is a relatively newly identified pathogen that is responsible for several respiratory conditions such as, pneumonia and chronic obstructive pulmonary disease and has been strongly linked to heart disesae. Serious disease is due to low grade chronic infections, but we do not understand how the bacterium causes these chronic diseases. This project will identify markers of chronic C. pneumoniae infections and relate these to the disease that results. Identifying these markers o ....Chlamydia pneumoniae is a relatively newly identified pathogen that is responsible for several respiratory conditions such as, pneumonia and chronic obstructive pulmonary disease and has been strongly linked to heart disesae. Serious disease is due to low grade chronic infections, but we do not understand how the bacterium causes these chronic diseases. This project will identify markers of chronic C. pneumoniae infections and relate these to the disease that results. Identifying these markers of chronic disease should lead to improved methods of disease control, including new diagnostic tests, vaccines and new drug therapies.Read moreRead less
Characterisation Of A Novel Type Of Promoter Controlling Expression Of Virulence Genes In Neisseria.
Funder
National Health and Medical Research Council
Funding Amount
$200,880.00
Summary
This project will investigate how two different types of bacteria control genes that are involved in determining their disease-causing ability. The expression of many bacterial genes is controlled by a sophisticated battery of regulatory systems that respond to individual, very specific, environmental signals. Such regulatory systems are capable of exerting very precise control over the level of gene expression, in response to the concentration of specific molecules in the immediate environment. ....This project will investigate how two different types of bacteria control genes that are involved in determining their disease-causing ability. The expression of many bacterial genes is controlled by a sophisticated battery of regulatory systems that respond to individual, very specific, environmental signals. Such regulatory systems are capable of exerting very precise control over the level of gene expression, in response to the concentration of specific molecules in the immediate environment. However, there is evidence to suggest that many important disease-causing bacteria are much less reliant on specific regulatory systems. Instead, these bacteria rely more heavily what have been termed global systems for the regulation of gene expression. Such systems typically respond to less specific signals, such as the growth rate of the bacterial cell, but nevertheless appear capable of very precise control. We have evidence for a previously uncharacterised type of global control system that appears to be widespread amongst bacteria. It is likely that many virulence genes in a variety of disease-causing bacteria will prove to be controlled by similar means. Therefore this project will not only provide an insight into how expression of these particular virulence determinants is regulated, but will yield data that may help in our understanding of precise global regulatory processes in other bacterial species of medical importance.Read moreRead less
A group of bacteria called Neisseria cause human-specific infections. To initiate infection, the bacteria must produce a hair-like surface structure, the pilus. The pilus consists mainly of a protein called pilin, and we now understand how pilin production is controlled. However 20 other genes are also involved in pilus production. This project aims to understand how these other genes are controlled and coordinated to assemble this structure that is central to the ability to cause disease.
Virulence And Oxidative Stress In Streptococcus Pneumoniae
Funder
National Health and Medical Research Council
Funding Amount
$110,125.00
Summary
Streptococcus pneumoniae is an important human pathogen that causes pneumonia, meningitis and bacteraemia as well as otitis media in young children. It is a cause of high morbidity and mortality around the world. S. pneumoniae grows by fermentative metabolism, a characteristic of anaerobic organisms, but it is able to adapt towards oxygen in the environment. This adaptive ability enables S. pneumoniae to live under conditions of high oxygen tension (eg. the upper respiratory tract) or under almo ....Streptococcus pneumoniae is an important human pathogen that causes pneumonia, meningitis and bacteraemia as well as otitis media in young children. It is a cause of high morbidity and mortality around the world. S. pneumoniae grows by fermentative metabolism, a characteristic of anaerobic organisms, but it is able to adapt towards oxygen in the environment. This adaptive ability enables S. pneumoniae to live under conditions of high oxygen tension (eg. the upper respiratory tract) or under almost anaerobic conditions (eg. the middle ear) in the human body. The emergence of antibiotic resistant pneumococci and limitations of current vaccines has led to increased interest in understanding the molecular mechanisms of pathogenesis of this bacterium. Of particular interest has been the pneumococcal surface antigen PsaA, which has been shown to be a protective immunogen in mice. It has also been shown that psaA mutants exhibit massively reduced virulence in mice in intranasal and intraperitoneal challenge models. Taken together, these data have led to the suggestion that PsaA might be an effective vaccine antigen or antimicrobial target. We postulate that PsaA is involved in the oxidative stress response and virulence under aerobic conditions and have devised a study to determine the procise role of this protein in disease caused by Streptococcus pneumoniae.Read moreRead less
Global Regulation Of Toxin Production In Clostridium Perfringens
Funder
National Health and Medical Research Council
Funding Amount
$389,860.00
Summary
This project involves an investigation of how the bacteria that cause an often fatal wound infection control the production of the toxic proteins that are essential elements of the disease process. In all pathogenic bacteria there are specific genes that encode the virulence factors that are involved in the disease. The expression of these genes is generally controlled by the products of other genes known as regulatory genes. The function of these regulatory networks is generally responsive to e ....This project involves an investigation of how the bacteria that cause an often fatal wound infection control the production of the toxic proteins that are essential elements of the disease process. In all pathogenic bacteria there are specific genes that encode the virulence factors that are involved in the disease. The expression of these genes is generally controlled by the products of other genes known as regulatory genes. The function of these regulatory networks is generally responsive to environmental stimuli. This project involves the detailed functional analysis of a regulatory network that was first identified in this laboratory and which controls the expression of extracellular toxins that have been implicated in gas gangrene. The overall objectives of the project are to develop a detailed understanding of the mechanisms involved in this regulatory process. Specifically, the project aims to determine the functional components of the regulatory proteins that interact with the environmental signal or which bind to the genes encoding the bacterial toxins, to determine the nature of the target sites to which the regulatory proteins bind, and to examine the hypothesis that there is another regulatory gene that is involved in this process. The project will make a major contribution to our knowledge of the complex interactions that occur between an invading bacterium and the host tissues. If we are to fully comprehend how bacteria cause disease then it is critical that we understand how bacteria control the production of the toxic products that are an integral part of the disease process.Read moreRead less
Multidrug Resistance Regulatory Protein QacR From Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$459,750.00
Summary
One of the most significant mechanisms of drug resistance is the export of antibiotics and other chemotherapeutic drugs from the cell. Drug export systems are an important medical problem due to their frequent occurrence in bacteria and parasites which cause human disease, and in human cancer cells. Proteins which recognise and export a broad range of drugs from a cell are called multidrug efflux pumps. These multidrug efflux systems present a serious threat to patient care and to successful the ....One of the most significant mechanisms of drug resistance is the export of antibiotics and other chemotherapeutic drugs from the cell. Drug export systems are an important medical problem due to their frequent occurrence in bacteria and parasites which cause human disease, and in human cancer cells. Proteins which recognise and export a broad range of drugs from a cell are called multidrug efflux pumps. These multidrug efflux systems present a serious threat to patient care and to successful therapy, since the ability to produce a single protein simultaneously renders the cell or organism resistant to several different drugs. Strains of the bacterial pathogen Staphylococcus aureus or Golden Staph, which are endemic in hospitals world-wide, contain an example of such a multidrug exporter, the QacA multidrug efflux pump. QacA exports at least 30 different antimicrobial compounds, including antiseptics and disinfectants. Production of this protein is regulated by a sensor protein, QacR, which detects the presence of a number of these antimicrobial compounds. To understand how the QacR sensor protein can recognise such a wide variety of compounds, we will identify and structurally characterise the regions of the QacR multidrug regulatory protein which bind these compounds. Additionally, we will examine the means by which QacR regulates the production of the QacA pump protein. This project will provide fundamental knowledge that will not only help with understanding the important process of multidrug resistance but will also enable the rational design of more effective antibacterial compounds that either block or evade these multidrug efflux systems.Read moreRead less
GENETIC ANALYSIS OF POLYSACCHARIDE CAPSULE BIOSYNTHESIS AND REGULATION IN STREPTOCOCCUS PNEUMONIAE
Funder
National Health and Medical Research Council
Funding Amount
$377,036.00
Summary
Streptococcus pneumoniae (the pneumococcus) is an important cause of invasive diseases such as pneumonia, meningitis and bacteraemia in humans. Many people carry this organism in the nasopharynx asymptomatically. However, in a small proportion, the organism overcomes host defences and invades the body causing life-threatening disease. An essential virulence factor of the pneumococcus is the polysaccharide capsule which protects it from the immune defences of the host during an infection. Until r ....Streptococcus pneumoniae (the pneumococcus) is an important cause of invasive diseases such as pneumonia, meningitis and bacteraemia in humans. Many people carry this organism in the nasopharynx asymptomatically. However, in a small proportion, the organism overcomes host defences and invades the body causing life-threatening disease. An essential virulence factor of the pneumococcus is the polysaccharide capsule which protects it from the immune defences of the host during an infection. Until recently, very little was known of the pneumococcal genes involved in production of this antigen. This project aims to continue characterization of these genes, and examination of the factors which regulate their expression. This regulatory mechanism may be very important, because production of increased levels of the polysaccharide capsule is believed to be an crucial step in the transition from carriage to invasion. An understanding of the molecular events involved in biosynthesis and regulation of capsule production will improve our understanding of the disease process and identify alternative targets for antimicrobial therapy.Read moreRead less