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The Glyco-interactome Of Pathogenic Neisseria: Understanding Disease And Defining Vaccine Targets
Funder
National Health and Medical Research Council
Funding Amount
$431,012.00
Summary
In order to infect humans and cause disease, many bacteria rely on interactions with carbohydrate (sugar) structures on human cells. This project aims to characterise the sugar interactions that enable Neisseria meningitidis (causes meningitis, sepsis) and Neisseria gonorrhoeae (causes gonorrhoea, associated with infertility and increased transmission of HIV) to cause disease. This will increase our understanding of host-pathogen interactions and aid development of new vaccines and therapeutics.
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.
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
Vaccine Discovery For Human Mucosal Pathogens: Identifying Novel Vaccine Antigens That Are Stably Expressed During Host Interactions, Using Analysis Of Cell-contact And Phasevarion Mediated Expression Profiles
Funder
National Health and Medical Research Council
Funding Amount
$418,482.00
Summary
The control of several human pathogens depends on vaccine development due to antibiotic resistance and the devastating outcome of infection. This work aims to identify new vaccine targets for diseases including gonorrhoae, ear infections, meningitis and sepsis, based on proteins required for interaction with human cells. Proteins that are randomly switched on and off in these bacteria will also be studied to better understand disease and to rule out variably expressed genes from new vaccines.
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.
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
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.
Phase Variable Protein Glycosylation In Bacteria Mucosal Pathogens And Its Role In Immune Evasion
Funder
National Health and Medical Research Council
Funding Amount
$409,728.00
Summary
The bacterium Haemophilus influenzae is a leading cause of ear infections. Hearing loss from these infections can seriously affect literacy and educational performance. As no vaccine is available, we will research how the bacterium makes the HMW protein that is important in infection. We will study how sugars are added to the surface of this protein so that the bacterium can escape the immune system, its role in related bacteria and how it may be used in a vaccine.
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.