Regulatory Networks Controlling The Interaction Of Neisseria Gonorrhoeae With The Human Host
Funder
National Health and Medical Research Council
Funding Amount
$361,091.00
Summary
What does Neisseria gonorrhoeae switch on when entering a human cell? Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease (STD) gonorrhoea and globally causes approximately 20-60 million new cases per annum (WHO). Gonococcal infection is the leading cause of pelvic inflammatory disease in women and ~ one third of patients will become infertile. Increased levels of resistance to traditional antibiotics have raised concerns for future treatment options. To date no succ ....What does Neisseria gonorrhoeae switch on when entering a human cell? Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease (STD) gonorrhoea and globally causes approximately 20-60 million new cases per annum (WHO). Gonococcal infection is the leading cause of pelvic inflammatory disease in women and ~ one third of patients will become infertile. Increased levels of resistance to traditional antibiotics have raised concerns for future treatment options. To date no successful vaccine strategies have been developed for this organism, primarily because the cell surface proteins elicit limited immunological protection against other strains. To enable the development of innovative approaches to the control of gonococcal infections, we propose to investigate the regulatory networks in gonococci that are important for initial colonization and survival in the human host. We will examine the role of a class of proteins, called sigma factors, that control the expression of a large number of genes in a concerted fashion. The sigma factors themselves do not recognize environmental signals, but their activity is controlled by a complicated array of proteins that are responsive to changing conditions in the bacterial cell. We have for the first time in any bacterial pathogen, identified all of the genes controlled by sigma factors in the obligate human pathogen, Neisseria gonorrhoeae. We have also found that the mechanisms controlling the activity of the sigma factors in this organism are different to those found in other bacterial pathogens. Our aim is to understand the mechanisms that control sigma factors and to gain insight into how N. gonorrhoeae sense and responds to the host cell during infections.Read moreRead less
Urinary tract infections (UTI) are among the most common infectious diseases of humans and a major cause of morbidity and mortality. In the USA, UTI accounts for >$1.6 billion in medical expenses each year. It is estimated that 50% of women will develop a UTI in their lifetime. This research aims to understand the processes by which bacteria colonize the human bladder. The work has implications for the development of new approaches to prevent and treat UTI.
Uropathogenic Escherichia coli (UPEC) are a major cause of urinary tract infections (UTI) and sepsis. Recently, a highly virulent clone of UPEC (E. coli ST131) that is resistant to multiple types of antibiotics has emerged worldwide. This project addresses the mechanisms by which E. coli ST131 can colonise the urinary tract and cause disease. The outcomes of this project will be a better understanding of how E. coli ST131 causes disease, and potentially new treatment regimes for UTI.
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.
Molecular Characterization Of E. Coli That Cause Urinary Tract Infection
Funder
National Health and Medical Research Council
Funding Amount
$387,114.00
Summary
The long term goals of the proposed research are to understand the processes by which uropathogenic Escherichia coli (UPEC) cause acute, recurrent and chronic infections and to identify new UPEC targets for therapeutic intervention. Urinary tract infections (UTI) are among the most common infectious diseases of humans and a major cause of morbidity and mortality. In the USA, UTI accounts for more than 1 million hospitalizations and $1.6 billion in medical expenditures each year. It is estimated ....The long term goals of the proposed research are to understand the processes by which uropathogenic Escherichia coli (UPEC) cause acute, recurrent and chronic infections and to identify new UPEC targets for therapeutic intervention. Urinary tract infections (UTI) are among the most common infectious diseases of humans and a major cause of morbidity and mortality. In the USA, UTI accounts for more than 1 million hospitalizations and $1.6 billion in medical expenditures each year. It is estimated that one in four women and one in twenty men will develop a UTI in their lifetime. The recurrence rate is high and no treatment other than antibiotics (often inefficient) is currently available. UPEC are the primary cause of UTI. In the last grant period, we focused on the molecular interplay that exists between different surface adhesins of UPEC. We succeeded in demonstrating functional interference between adhesins, motility organelles, aggregation factors and the capsule. We also discovered and partially characterized several novel UPEC adhesins that may play a role in pathogenesis. We established two novel technology sets: a mouse model of ascending UTI and the flow chamber biofilm model. In the next grant period, we will build on these concepts and experimental systems to gain a deeper understanding of the molecular mechanisms underlying UPEC virulence. We will characterize the role of several novel UPEC surface proteins in cell adhesin, aggregation, biofilm formation and colonization of the mouse urinary tract. We will employ an integrated approach that combines a powerful bacterial genetic system, a biofilm model, a mouse UTI model, microscopy and tissue culture systems to reveal the cellular, molecular, and structural basis for the pathogenesis of UTI. The work will facilitate the development of new vaccine approaches to prevent UTI, such as novel mechanisms for strain attenuation and vaccine design. The burden of UTI disease demands such research endeavours.Read moreRead less
Virulence Mechanisms In Hypervirulent Epidemic Strains Of Clostridium Difficile.
Funder
National Health and Medical Research Council
Funding Amount
$499,135.00
Summary
The bacterium Clostridium difficile is the major cause of nosocomial diarrhoea in many countries, including Australia. More virulent isolates have emerged since 2000, leading to increased incidence and severity of disease in many countries and resulting in epidemics. This project will make a major contribution to our understanding of how these bacteria cause disease and may help to prevent outbreaks of the hypervirulent strains in Australia by identifying potential new vaccine candidates.
Characterising The Role Of Streptokinase Polymorphism In Invasive Pathogenesis Of Streptococcus Pyogenes.
Funder
National Health and Medical Research Council
Funding Amount
$480,535.00
Summary
Invasive bacterial pathogens such as Streptococcus pyogenes, can hijack host proteins and use them to facilitate the disease process. S. pyogenes secrete streptokinase to activate a host protease (plasminogen) which is used by the bacterium to invade through host tissue. This project will characterise the molecular mechanisms involved in streptokinase mediated activation of plasminogen which will assist the generation of novel therapeutics to treat invasive diseases.
Molecular Basis Of Asymptomatic Colonization Of The Human Urinary Tract
Funder
National Health and Medical Research Council
Funding Amount
$461,894.00
Summary
Urinary tract infections (UTI) are among the most common infectious diseases of humans and a major cause of morbidity and mortality. In the USA, UTI accounts for >$1.6 billion in medical expenses each year. It is estimated that 50% of women will develop a UTI in their lifetime. This research aims to understand the processes by which bacteria colonize the human bladder and the surface of urinary catheters. The work has implications for the development of new approaches to prevent and treat UTI ....Urinary tract infections (UTI) are among the most common infectious diseases of humans and a major cause of morbidity and mortality. In the USA, UTI accounts for >$1.6 billion in medical expenses each year. It is estimated that 50% of women will develop a UTI in their lifetime. This research aims to understand the processes by which bacteria colonize the human bladder and the surface of urinary catheters. The work has implications for the development of new approaches to prevent and treat UTI.Read moreRead less
Polymicrobial Interactions In A Biofilm Of Periodontopathic Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$474,517.00
Summary
Chronic periodontitis is a bacterial-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. Three bacterial species in a biofilm (dental plaque) have been closely associated with chronic periodontitis in human ....Chronic periodontitis is a bacterial-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. Three bacterial species in a biofilm (dental plaque) have been closely associated with chronic periodontitis in humans and a fourth bacterial species has been suggested to assist colonisation of the biofilm by the three pathogenic species. The aim of this project is to use DNA microarray and proteomic techniques to study the interaction of the four bacterial species grown together in a polymicrobial biofilm. In particular genes of two of the pathogens, Porphyromonas gingivalis and Treponema denticola, important for biofilm formation and virulence in an animal model will be identified. This information will provide insight into the molecular processes of dental plaque formation and therfore molecular targets for the development of specific inhibitors that may have utility in the treatment and prevention of chronic periodontitis.Read moreRead less