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.
Characterisation Of A Newly-discovered, Virulence-associated, Protein Secretion System Of Enteropathogenic E. Coli
Funder
National Health and Medical Research Council
Funding Amount
$582,149.00
Summary
The cell walls of bacteria act as a barrier to the export of any proteins they produce. We recently discovered a protein secretion system, which diarrhoea-causing strains of E. coli require to cause disease. The aim of this study is to characterise this secretory system, and discover how it functions and what it secretes. The knowledge obtained from this research will shed new light on how E. coli causes disease and could reveal novel methods to treat and prevent infections with this bacterium.
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.
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
Development Of Improved Preventative Therapeutic Strategies For The Control Of Infectious Disease
Funder
National Health and Medical Research Council
Funding Amount
$4,000,000.00
Summary
A major objective of this Australia Fellowship application is to provide a mechanism whereby, for the first time in my career, I can devote myself full-time to my program of research. This program addresses an issue of global significance, namely the control of bacterial infectious diseases. These continue to cause massive global morbidity and mortality and constitute a profound threat to human health, in spite of the availability of antimicrobial drugs for over 60 years. WHO estimates that bact ....A major objective of this Australia Fellowship application is to provide a mechanism whereby, for the first time in my career, I can devote myself full-time to my program of research. This program addresses an issue of global significance, namely the control of bacterial infectious diseases. These continue to cause massive global morbidity and mortality and constitute a profound threat to human health, in spite of the availability of antimicrobial drugs for over 60 years. WHO estimates that bacterial infections are responsible for >10 million deaths p.a., and the economic impact is inestimable. For most major pathogens, vaccines are either unavailable or have serious shortcomings. Resistance to commonly used antimicrobials is increasing at an alarming rate, and modern travel has assisted the rapid global dissemination of highly resistant and virulent clones. Morbidity and mortality are also predicted to increase as a consequence of human-induced environmental changes and the growing proportion of the population with increased susceptibility to infection. Effective management of bacterial infectious diseases in the 21st century will require a two-pronged approach involving the development of cheaper and more effective vaccines, as well as novel anti-infectives refractory to known resistance mechanisms. However, formulation of optimal therapeutic and preventative strategies demands a thorough understanding of the biology of disease, particularly the complex interactions between bacterial pathogens and their human hosts. I have also played a leadership role in establishing the Pneumococcal Vaccine Consortium, which has just submitted a co-ordinated suite of multicentre proposals to PATH Vaccine Solutions to fund final preclinical testing, GMP scale-up and Phase I-II-III trials of protein-based pneumococcal vaccines that we have developed. The PATH accelerated pneumococcal vaccine development program is of enormous potential significance, because there is now a very real probability of pneumococcal protein vaccines being fast-tracked into human trials. Our aim is to create a direct pipeline from antigen discovery in the collaborators’ laboratories into the clinic. If successful, these vaccines could save millions of lives. This will be of enormous satisfaction to me personally, as it was I who originally proposed and demonstrated “proof of principle” for the vaccine potential of pneumococcal proteins, and I have been advocating assessment of their protective efficacy in humans for over 20 years. Thus, receipt of an Australia Fellowship will undoubtedly further support the internationalisation of Australian medical research.Read moreRead less
The Regulation Of IgE Antibody Production By Antigen-specific B Cells
Funder
National Health and Medical Research Council
Funding Amount
$454,105.00
Summary
Asthma and other allergies are caused by the inappropriate production of IgE antibodies by the immune system. IgE is not produced in response to most infections but the controls that normally prevent IgE production are unknown. We have identified two separate molecules that prevent IgE production during immune responses. In this proposal we aim to investigate how these controls work. This information may help to devise strategies for controlling IgE production and therefore allergic disease.
Analysis And Regulation Of Leptospiral Virulence Factors.
Funder
National Health and Medical Research Council
Funding Amount
$630,465.00
Summary
Leptospirosis is a globally important infectious disease caused by Leptospira spp. This project aims to identify and characterise factors which play a role in disease development by knocking out genes, then investigating the impact on overall gene-protein expression in the mutant strain and its ability to cause disease. This will allow us to gain insights on mechanisms by which Leptospira spp. cause disease, leading to development of better methods of disease control and prevention.
Outer Membrane Proteins Of Leptospira; Role In Immunity And Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$88,500.00
Summary
Leptospirosis is a significant cause of death in tropical regions of the world. Recent outbreaks in Nicaragua and Brazil are timely reminders of the seriousness of disease caused by the Leptospira bacteria. In these outbreaks >10% of people developing the disease did not recover. Spread of the disease does not occur from person to person, but rather from animal to human. Leptospira are shed from infected animals via the urine; human infection may occur through contact with infected urine or u ....Leptospirosis is a significant cause of death in tropical regions of the world. Recent outbreaks in Nicaragua and Brazil are timely reminders of the seriousness of disease caused by the Leptospira bacteria. In these outbreaks >10% of people developing the disease did not recover. Spread of the disease does not occur from person to person, but rather from animal to human. Leptospira are shed from infected animals via the urine; human infection may occur through contact with infected urine or urine contaminated materials. In Australia, leptospirosis is an occupational hazard with dairy farmers, pig handlers, banana pickers and abattoir workers being those most at risk. A recent and alarming development is the emergence of new risk groups associated with certain leisure activities. For example, in the USA three triathletes died from leptospirosis and it was subsequently determined that the source of infection was contaminated swimming water. This project will investigate aspects of the development of disease and immunity during infection by Leptospira. This will be achieved by analysing the set of proteins located on the surface of the bacterium. These proteins play a key role in the development of disease. Using state of the art technology, each of the proteins will be purified and identified. This will enable experiments that will enhance our understanding of the development of disease at a molecular level.Read moreRead less
Contribution Of Shigella And Escherichia Coli Pathogenicity Islands To Diarrhoeal Disease
Funder
National Health and Medical Research Council
Funding Amount
$303,677.00
Summary
Diarrhoea resulting from infection with Shigella and Escherichia coli is a major cause of sickness and death in the developing world, especially in children. Even in Australia, these bacteria, which may be food borne, are occasionally responsible for life threatening infections. In this study, we will investigate the contribution to diarrhoeal disease of large fragments of foreign DNA which have been recently acquired by these bacteria. We will characterise several of these elements in detail, i ....Diarrhoea resulting from infection with Shigella and Escherichia coli is a major cause of sickness and death in the developing world, especially in children. Even in Australia, these bacteria, which may be food borne, are occasionally responsible for life threatening infections. In this study, we will investigate the contribution to diarrhoeal disease of large fragments of foreign DNA which have been recently acquired by these bacteria. We will characterise several of these elements in detail, identifying novel virulence determinants and toxins in the process. We will also explore the means by which these packages of nasty DNA transfer between bacteria and investigate their potential to give rise to new, more virulent strains of bacteria. This study is particularly significant because it will lead to an improved understanding of how bacteria cause disease and may help to guide us in developing better strategies for the prevention of bacterial diarrhoea. Specifically, the work done on characterising large clusters of virulence genes will allow us to construct safer bacterial vaccines and we expect that in the future this knowledge will contribute to the development of new and better diagnostic and therapeutic agents against these harmful bacteria.Read moreRead less