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
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
Glycosylation Of Pili In Pathogenic Neisseria: Function In Disease And Potential As A Vaccine Antigen
Funder
National Health and Medical Research Council
Funding Amount
$150,880.00
Summary
Disease caused by Group B Neisseria meningitidis and Neisseria gonorrhoeae remain a significant health problem worldwide. There are currently no vaccines available for either of these bacteria. A surface structure found on these bacteria, called pili, are key in host colonisation and disease. Genetics and structural studies have identified that the protein subunits, which make up pili, are glycosylated - modified by the addition of sugars. The role of glycosylation in the disease process is not ....Disease caused by Group B Neisseria meningitidis and Neisseria gonorrhoeae remain a significant health problem worldwide. There are currently no vaccines available for either of these bacteria. A surface structure found on these bacteria, called pili, are key in host colonisation and disease. Genetics and structural studies have identified that the protein subunits, which make up pili, are glycosylated - modified by the addition of sugars. The role of glycosylation in the disease process is not known. It is possible that the glycosylation of pili is required for attachment to host cells or perhaps in evasion of the immune system. In our current studies, we have identified and analysed a number of genes involved in pili glycosylation, in bacteria which make structre that are know. We have also identified a series of new genes we believe are also involved in glycosylation. Some of these genes are involved in the biosynthesis of unknown structures and are common in bacteria isolated from patients with meningitis. We will identify these stuctures and characterise bacteria in which these genes have been inactivated so that we can examine the role of pili glycosylation in colonisation and disease. This study has the potential to yield important new information about the process of colonisation and disease, and also has the potential to facilitate novel approaches in vaccine development.Read moreRead less
Streptococcus pneumoniae (the pneumococcus) is an important human pathogen, which is responsible for the deaths of millions of children each year in developing countries. The high morbidity and mortality associated with pneumococcal disease is also being exacerbated by the rate at which this organism is acquiring resistance to multiple antibiotics. Existing pneumococcal polysaccharide vaccines are poorly immunogenic in young children and only provide cover against a limited range of serotypes. S ....Streptococcus pneumoniae (the pneumococcus) is an important human pathogen, which is responsible for the deaths of millions of children each year in developing countries. The high morbidity and mortality associated with pneumococcal disease is also being exacerbated by the rate at which this organism is acquiring resistance to multiple antibiotics. Existing pneumococcal polysaccharide vaccines are poorly immunogenic in young children and only provide cover against a limited range of serotypes. Serotype coverage is even lower in the more immunogenic conjugate vaccines currently being developed; these will also be very expensive, thereby limiting their use in developing countries, where the need for effective paediatric vaccines is greatest. Pneumococci produce a variety of proteins which are important in causing disease, but the relative contribution of these factors at each stage of the infection process remain to be determined. Moreover, virtually nothing is known of the mechanism whereby these virulence factors are regulated in response to the external environment of the bacterium. In view of this, we are conducting a comprehensive examination of the mechanisms of pathogenesis of pneumococcal disease, with particular reference to the role of putative virulence proteins. This information is being used to develop cheap and effective vaccines based on pneumococcal protein antigens common to all serotypes.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
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