Dissemination And Virulence Properties Of The She Pathogenicity Island Of Shigella Flexneri.
Funder
National Health and Medical Research Council
Funding Amount
$110,625.00
Summary
Bacterial species belonging to the genus Shigella are responsible for intestinal diseases ranging from mild diarrhoea to life threatening bacillary dysentery. Such diseases kill over a million people, mainly infants in developing countries, every year and lead to serious morbidity and mortality even in industrialised countries with well developed health care systems. In many cases the virulence of Shigella species is augmented by large fragments of DNA, called pathogenicity islands, that carry g ....Bacterial species belonging to the genus Shigella are responsible for intestinal diseases ranging from mild diarrhoea to life threatening bacillary dysentery. Such diseases kill over a million people, mainly infants in developing countries, every year and lead to serious morbidity and mortality even in industrialised countries with well developed health care systems. In many cases the virulence of Shigella species is augmented by large fragments of DNA, called pathogenicity islands, that carry genes which contribute to the development of disease (pathogenesis) in humans. Pathogenicity islands are important genetic elements which appear to spread independantly throughout bacterial populations and therefore contribute to the emergence of new virulence traits in bacteria. Recently, we identified two related pathogenicity islands carried by both Shigella flexneri and other species of the genus Shigella. The two pathogenicity islands belong to a unique class of genetic elements found in Shigella species and virulent strains of the intestinal bacterium E. coli. Our current study is aimed at (1) understanding the mechanisms by which one of these islands, the she pathogenicity island, spreads from one bacterial strain to another to introduce disease-producing or virulence genes to new bacteria and (2) to study how the sigA virulence gene, carried on the she pathogenicity island, contributes to disease development in humans. We know that sigA encodes a protein toxin which contributes to the loss of fluid from the intestines of rabbits that have been experimentally infected with Shigella flexneri. We propose to study the structure and function of the SigA protein to determine how it interacts with tissues to produce a pathological state. Such studies will enhance our understanding of the process of disease development and contribute to the investigation and assessment of new strategies for therapeutic intervention.Read moreRead less
Dissecting The Contribution Of Malaria Translocon Components To Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$326,583.00
Summary
The malaria parasite exports hundreds of proteins into its host red blood cell via a unique protein export machinery. This enables the parasite to avoid immune detection, resulting in over one million deaths annually. This proposal will use a rodent malaria infection model to address the functional significance and contribution of the machinery to malaria disease to discern if it will provide a potential target for anti-malaria drugs.
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
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
Utilising Transgenesis To Investigate The Role Of Insulin Signaling In Helminthic Infections
Funder
National Health and Medical Research Council
Funding Amount
$316,336.00
Summary
Helminth parasites take an enormous toll on human health, especially in developing countries. Half a billion people suffer debilitating, sometimes fatal illness as a result of these infections. These facts are all the more disturbing when one considers the prospect of nematode parasites developing resistance to the small armamentarium of drugs available for treatment. This proposal will look to further understand the biology of these parasites in order to better comprehend what genes would make ....Helminth parasites take an enormous toll on human health, especially in developing countries. Half a billion people suffer debilitating, sometimes fatal illness as a result of these infections. These facts are all the more disturbing when one considers the prospect of nematode parasites developing resistance to the small armamentarium of drugs available for treatment. This proposal will look to further understand the biology of these parasites in order to better comprehend what genes would make for practical drug or vaccine targets.Read moreRead less
Identifying The Physiological Conditions That Promote Lateral Gene Transfer And Evolution Of New Streptococcal Pathovars
Funder
National Health and Medical Research Council
Funding Amount
$415,907.00
Summary
In the last few decades, the diseases caused by the three human pathogens, groups A, B and G streptococcus have undergone a transformation. The exchange of DNA between these species is speculated to play a role in this changing disease association. In this proposal we will identify the specific physiological and growth conditions that promote DNA transfer. Such information may help in our understanding of how new pathogenic strains of streptococci arise.
Defining The Role Of Plasminogen Activation In Group A Streptococcal Invasive Disease
Funder
National Health and Medical Research Council
Funding Amount
$425,763.00
Summary
The "flesh-eating" bacteria group A streptococcus (GAS) causes life threatening invasive diseases such as necrotizing fasciitis and toxic shock syndrome (>600,000 cases and 163,000 deaths per year). For some types of GAS, plasminogen binding is essential for virulence.The aim of this work is to determine the extent to which plasminogen binding contributes to disease caused by highly virulent GAS. These studies will allow the development of new therapeutics and treatments.
Novel Therapeutic And Preventive Strategies For Clostridium Difficile Infections.
Funder
National Health and Medical Research Council
Funding Amount
$508,556.00
Summary
The bacterium Clostridium difficile is the major cause of nosocomial diarrhoea in many countries, including Australia. More virulent isolates have recently emerged, leading to increased incidence and disease severity in many countries. This project will make a major contribution to our understanding of how these bacteria cause disease. Preventive or treatment measures based on these research findings will help to prevent or lessen the severity of any epidemics that occur in Australia.
Fungi are increasingly causing life-threatening infections. Little is known about the mechanisms underlying these infections. We will compare the genomes of high and low virulent fungal strains to gain insides into the basis of these differences by using C. gattii as model of a globally highly pathogenic fungus. The findings will be generalized by comparing the obtained results with the genomes of other important pathogenic fungi to develop a scientific basis for better treatment strategies.