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
Malaria is one of the worlds most significant health problems and is caused by protozoan parasites of the genus Plasmodium. We aim to understand the biology, pathogenesis, and epidemiology of P. falciparum and P. vivax infections together with a strong translational direction. Our studies will thus lead to the discovery and development of novel tools aiding in the renewed efforts for the global elimination of malaria.
Understanding Virulence Of Invasive Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$772,711.00
Summary
Staph aureus (Golden staph) is a major cause of disease in humans. In this project we will use state-of-the-art molecular biology and genomics to fully understand the mechanisms of virulence in this pathogen. This information will inform future approaches to development of therapeutics, as well as the use of genomics in clinical microbiology and disease management.
Systems-level Characterisation And Therapeutic Targeting Of Small RNAs In Acinetobacter Baumannii Disease
Funder
National Health and Medical Research Council
Funding Amount
$581,990.00
Summary
This proposal aims to understand how a superbug that causes severe infections in hospitalised patients worldwide and is known to be resistant to almost all available antibiotics, causes disease. We then plan on using this information to guide the development of a new type of therapy to treat this severe infection.
Modulation Of Apoptosis By Cytomegalovirus: Analysis Of New Mechanisms To Interfere With Cytomegalovirus-induced Disease
Funder
National Health and Medical Research Council
Funding Amount
$697,084.00
Summary
Apoptosis, or programmed cell death is an essential process in developmental and homeostatic control of complex biological systems. In addition to these primary house keeping roles, apoptosis provides a powerful defence mechanism against invading pathogens, such as viruses, since it allows early elimination of infected cells from the host. A basic property of herpesviruses is their ability to establish persistent infection and remain in association with the host for its lifetime. This strongly u ....Apoptosis, or programmed cell death is an essential process in developmental and homeostatic control of complex biological systems. In addition to these primary house keeping roles, apoptosis provides a powerful defence mechanism against invading pathogens, such as viruses, since it allows early elimination of infected cells from the host. A basic property of herpesviruses is their ability to establish persistent infection and remain in association with the host for its lifetime. This strongly underlines their success at reaching an accommodation with the immune system's anti-apoptotic mechanisms. The central hypothesis of this project is that herpesviruses, such as murine and human cytomegalovirus, encode proteins that interfere with cell death pathways thereby circumventing host defence so that viral replication and dissemination can proceed. Thus, the aims are to identify and characterise cytomegalovirus proteins that modulate apoptosis. These studies will improve our understanding of the control of apoptosis during viral infection, especially as caused by cytomegaloviruses. Human cytomegalovirus (HCMV) is a pathogen able to cause significant morbidity and mortality in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. Hence, the proposed studies will allow the elucidation of molecular mechanisms that may be relevant to the pathogenesis of HCMV in man and will provide insights into the rational design of suitable antiviral drugs and vaccines. Understanding viral mechanisms of host immune evasion continues to improve our understanding of complex cellular pathways. Therefore, given that abnormal regulation of apoptosis is implicated in the development of degenerative conditions, cancer and autoimmune disease, the proposed studies will provide valuable insight towards the development of new therapies for these pathological conditions.Read moreRead less
MOLECULAR AND CELLULAR PATHOGENESIS OF HUMAN LIVER DISEASE
Funder
National Health and Medical Research Council
Funding Amount
$4,928,323.00
Summary
n humans, chronic liver diseases cause cirrhosis of the liver in some but not all individuals. This leads to protracted ill-health, complications (fluid retention in the abdomen, confusion, bloodstream infections, kidney failure, liver cancer) resulting in hospitalisation, liver transplantation and premature death. In Australia, cirrhosis is an important cause of death and of years of potential life lost, while liver cancer has recently doubled and is predicted to treble by 2020. The common caus ....n humans, chronic liver diseases cause cirrhosis of the liver in some but not all individuals. This leads to protracted ill-health, complications (fluid retention in the abdomen, confusion, bloodstream infections, kidney failure, liver cancer) resulting in hospitalisation, liver transplantation and premature death. In Australia, cirrhosis is an important cause of death and of years of potential life lost, while liver cancer has recently doubled and is predicted to treble by 2020. The common causes are hepatitis C, fatty liver disorders, alcohol and hepatitis B; when 2 of these are present together, there is a higher risk of cirrhosis. This program aims to unravel the pathological processes which cause cirrhosis at the molecular and cellular levels, in order to understand why some people are at higher risk. These processes could result from genetic predisposition, other constitutional factors (age, gender) or from lifestyle factors (overnutrition, inactivity, alcohol). The 3 chief investigators from Westmead s Millennium Institute and the Centenary Institute of Royal Prince Alfred Hospital are international experts in hepatitis C, non-alcoholic steatohepatitis (NASH) and other fatty liver disorders, autoimmune hepatitis, liver transplantation, and scarring processes that lead to cirrhosis of the liver. The new knowledge that will result from these studies will be used to help prevent people developing severe forms of chronic liver disease, and for treating cirrhosis if it has already occurred.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
Elucidating The Role And Potential For Therapeutic Targeting Of TLR7 In Emphysema And COPD
Funder
National Health and Medical Research Council
Funding Amount
$925,780.00
Summary
Emphysema is a major cause of illness and death and there are no effective treatments. It is caused by smoking that damages the airways and air sacs but how this occurs is not well understood. We have found that a new factor, called Toll-like receptor 7, is involved in emphysema. In this study we will now characterise its roles in this disease, work out how it induces emphysema and test new inhibitors (antibodies) that we have developed as treatments.
Functional Characterisation Of A Maurer's Cleft Protein Involved In Adhesion Of Malaria-infected Red Blood Cells
Funder
National Health and Medical Research Council
Funding Amount
$160,500.00
Summary
Malaria is a serious disease that affects half of the world's population and frequently kills humans after a bout of high fever and coma. Many of those who die are young children who live in areas of the world where health care is very poor. The effectiveness of drugs that we currently have available to prevent or treat malaria is rapidly reducing and there is no vaccine available to prevent people from catching the disease. Our research is important because in order to make better medicines for ....Malaria is a serious disease that affects half of the world's population and frequently kills humans after a bout of high fever and coma. Many of those who die are young children who live in areas of the world where health care is very poor. The effectiveness of drugs that we currently have available to prevent or treat malaria is rapidly reducing and there is no vaccine available to prevent people from catching the disease. Our research is important because in order to make better medicines for malaria we have to get to know more about how the malaria parasite makes people sick. The most vicious form of malaria is caused by a tiny parasite called Plasmodium falciparum that lives inside the red blood cells in our bodies. As these minute parasites grow, they make a lot of major changes to the red blood cells and as a result they become very stiff and sticky. This is very bad for the infected person because instead of flowing around the body like normal red blood cells, the infected cells become trapped in small veins and can no longer do their normal job. The ability of the parasite to redecorate red blood cells and make them stiff and sticky is what makes this type of malaria so dangerous, particularly when red cells get stuck in the brain. The research that we will do here will help us to understand the ways in which the malaria parasite sends out these sticky substances to the walls of red blood cells. Eventually, this will help us to find ways to stop the red blood cells from becoming sticky and prevent so many people from becoming very sick and dying with malaria.Read moreRead less
Adaptive Changes In HIV-1 Subtype C Envelope Glycoproteins Contributing To Pathogenicity.
Funder
National Health and Medical Research Council
Funding Amount
$427,648.00
Summary
HIV exists as multiple subtypes. The most commonly studied is type B (B-HIV). B-HIV is common in North America, Europe and Asia, but accounts for only a small fraction of HIV infections worldwide. Type C HIV (C-HIV) in Africa and Asia accounts for the majority of infections worldwide, yet very little is known about how C-HIV causes AIDS. We aim to understand how C-HIV causes AIDS. This is critical for development of drugs and vaccines specifically designed for those who are most urgently need.