Development Of A Vaccine For Genital Chlamydia Infections: Protection Against Transmission And Disease Pathology
Funder
National Health and Medical Research Council
Funding Amount
$322,245.00
Summary
Genital Chlamydia infections are the most common sexually transmitted infection in Australia with annual health costs of 90-160 million dollars. Ifection rates in 15-29 year olds are increasing at 15-20% per year. Antibiotics are currently the treatment of choice, however antibiotic resistance is increasing and most infections are asymptomatic and not treated in the absence of screening programs. The project aims to develop a genital Chlamydia vaccine using a combination of novel antigens.
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
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.
Genetic Dissection Of The Biogenesis And Function Of Type IV Fimbriae Of Pseudomonas Aeruginosa
Funder
National Health and Medical Research Council
Funding Amount
$407,545.00
Summary
Pseudomonas aeruginosa is a common bacterium which causes serious life-threatening infections of individuals with cystic fibrosis, AIDS or who have suffered severe burns or are undergoing cancer chemotherapy. This pathogen, and a number of other important infectious bacteria use surface filaments, called fimbriae, like grappling hooks to attach to the cells of the body and to move across host tissues. These fimbriae are produced in response to environmental conditions, and are assembled by a pro ....Pseudomonas aeruginosa is a common bacterium which causes serious life-threatening infections of individuals with cystic fibrosis, AIDS or who have suffered severe burns or are undergoing cancer chemotherapy. This pathogen, and a number of other important infectious bacteria use surface filaments, called fimbriae, like grappling hooks to attach to the cells of the body and to move across host tissues. These fimbriae are produced in response to environmental conditions, and are assembled by a process that is also used in the export of toxins and other pathogenic molecules. This project will characterise genes which specify and control this system, as a means to design better treatments against such bacteria, many of which are resistant to antibiotic treatment.Read moreRead less