Characterisation Of HiaNm, A Novel Outer Membrane From Neisseria Meningitidis; Vaccine Potential And Functional Studies
Funder
National Health and Medical Research Council
Funding Amount
$356,685.00
Summary
Meningococcal meningitis is a devastating illness which mostly affects children under 5 years. The clinical presentation is of a rapidly progressing disease with high rates of morbidity and mortality. This disease is caused by a bacterium, Neisseria meningitidis (the meningococcus). Vaccines are available against serogroup A and C strains of N. meningitidis, but not for group B strains, which cause the majority of disease in industrialised countries. We have recently identified a gene (designate ....Meningococcal meningitis is a devastating illness which mostly affects children under 5 years. The clinical presentation is of a rapidly progressing disease with high rates of morbidity and mortality. This disease is caused by a bacterium, Neisseria meningitidis (the meningococcus). Vaccines are available against serogroup A and C strains of N. meningitidis, but not for group B strains, which cause the majority of disease in industrialised countries. We have recently identified a gene (designated hiaNm) which encodes a new protein which is located on the surface of the bacterium, in the outer membrane. There has been an enormous body of work done on the immunology, biochemistry and genetics of all components of the outer membrane of Neisseria meningitidis. Therefore the discovery of this novel protein provides an exciting opportunity to take a new direction in vaccine development. For an effective vaccine, the target molecule must be present in most strains; we have already shown that the hiaNm gene is present in all strains examined. In this proposal we describe a study of the vaccine potential and biological function of the hiaNm gene product HiaNm. We will express the protein at high levels, immunise mice, and produce antibodies against HiaNm to discover whether they can protect mice against meningococcal disease. At the completion of this set of experiments we will be in an excellent position to assess the potential for the further development of HiaNm as a component of a meningococcal vaccine.Read moreRead less
Certain bacterial DNA repeats are prone to hyper mutation. Genes with these repeats, Contingency genes, are randomly switched on and off. This process, phase variation , generates diversity in a population. Recently we described a new class of contingency gene that methylates DNA. On-off switching of this gene leads to random switching of multiple genes; the phasevarion . We will define the impact of this system in bacteria causing meningitis and STDs.
Role In Disease And Vaccine Potential Of Cell Surface O-linked Glycoproteins In Pathogenic Neisseria.
Funder
National Health and Medical Research Council
Funding Amount
$212,347.00
Summary
Bacteria that have adapted to life exclusively in the human host have developed unique strategies to colonize the host and to evade the immune response. An emerging strategy is modification of bacterial surface proteins with sugars or other modifications. Our data suggests a key role for these modifications in disease. We will investigate how the modifications are made, discover structures of novel modifications and determine their precise role in disease.
The Immunogenicity Of 7-valent Pneumococcal Conjugate Vaccine In Sick Elderly People For Whom Vaccine Is Not Registered
Funder
National Health and Medical Research Council
Funding Amount
$443,800.00
Summary
The bacteria pneumococcus (also known as streptococcus pneumoniae) is the most common cause of pneumonia in the community, and a major cause of illness and death in the elderly. Rates of antibiotic resistance are also increasing. The pneumococcus is a complex bacteria, with over 80 known serotypes. Most human disease in Australia is caused by 23 of these serotypes. Australia has an ageing population. The health and wellbeing of the elderly has been identified as a national priority. Vaccination ....The bacteria pneumococcus (also known as streptococcus pneumoniae) is the most common cause of pneumonia in the community, and a major cause of illness and death in the elderly. Rates of antibiotic resistance are also increasing. The pneumococcus is a complex bacteria, with over 80 known serotypes. Most human disease in Australia is caused by 23 of these serotypes. Australia has an ageing population. The health and wellbeing of the elderly has been identified as a national priority. Vaccination and prevention of serious infections, a common cause of illness in the elderly, is an achievable public health goal. The National Health and Medical Research Council (NHMRC) of Australia recommends that adults aged 65 years and over should be immunised with 23-valent polysaccharide pneumococcal vaccine (PPV). PPV has been available long term in Australia, but the dilemma associated with its use is that it is least effective in those at greatest risk of pneumococcal disease and its complications, the sick elderly population. A new 7-valent pneumococcal conjugate vaccine (PCV-7) has been available since the end of 2000, but is currently indicated only for children, because it has never been tested in adults. This vaccine uses different technology, and is conjugated to a protein to make it more effective. Clinicals trials of PCV7 have largely been limited to children aged 0-4 years, and have shown it protects 93.9% of children under 2 years of age against invasive pneumococcal disease (IPD). Our study aims to look at the efficacy of this new vaccine, currently only registered for children, in the sub-group of the population who are at highest risk for pneumococcal disease - hospitalised elderly. We will vaccinate hospitalised elderly people with PCV or PPV and compare their immune response to the two different vaccines. If PCV is more effective than PPV, this has implications for the development and use of conjuagated pneumococcal vaccines for adults.Read moreRead less
The Molecular Physiology Of Streptococcus Pneumoniae During Sepsis
Funder
National Health and Medical Research Council
Funding Amount
$232,504.00
Summary
The project will determine the way in which pneumococcus changes its properties when it invades the bloodstream of the human host. Since these changes are linked to sepsis then this new understanding will provide information that can be used to manage and control acute pneumococcal infection.
The Role Of Protein Oxidation And Isomerization Pathways In The Pathogenesis Of Neisseria Meningitidis
Funder
National Health and Medical Research Council
Funding Amount
$264,816.00
Summary
Neisseria meningitidis causes meningococcal disease. It lives on the surface of the nasopharynx and in certain circumstances, can invade into the bloodstream causing sepsis. This is a complicated process, which involves many proteins produced by the bacteria. Many of these proteins contain a special covalent bond, the disulphide bond, which allows them to function properly. We are investigating how these disulphide bonds are put into proteins.
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.
Characterisation Of Antigenic Variation Of Neisserial Cell Surface Adhesins, And Their Role In Infection
Funder
National Health and Medical Research Council
Funding Amount
$556,983.00
Summary
A group of bacteria called Neisseria cause human-specific infections. They produce two types of surface proteins termed adhesins, which allow the bacteria to adhere to, and invade, human cells. There is circumstantial evidence to suggest the bacteria can rapidly vary the structure of these adhesins, even within a single infection. This project will determine whether, and how, this variation is occurring, and what effect it has on the ability of the bacteria to cause disease.