Cholera Toxin Co-receptor Interaction In The Prevention Of Inflammatory Autoimmune Disorders
Funder
National Health and Medical Research Council
Funding Amount
$359,577.00
Summary
Vaccination is undoubtedly one of mankind's greatest achievements. While infections continue to be the major cause of morbidity and mortality in the developing world, heart disease, cancer, chronic allergies and autoimmune disorders are taking their toll in advanced societies. Our expanding knowledge of these 'modern diseases' shows that the immune system plays a central role and hence it is important to learn if new immunologically-based therapies can be developed for such chronic human disorde ....Vaccination is undoubtedly one of mankind's greatest achievements. While infections continue to be the major cause of morbidity and mortality in the developing world, heart disease, cancer, chronic allergies and autoimmune disorders are taking their toll in advanced societies. Our expanding knowledge of these 'modern diseases' shows that the immune system plays a central role and hence it is important to learn if new immunologically-based therapies can be developed for such chronic human disorders. This project takes advantage of our recent discoveries on the immunological properties of a hitherto feared molecule - cholera toxin. We have shown that one portion of the toxin, the B-subunit, responsible for binding to cell membranes, possesses remarkable immunomodulatory properties that prevent the development of inflammatory autoimmune disorders such as rheumatoid arthritis in animal models. The B-subunit, in contrast to the whole cholera toxin, is non-toxic and has no adverse effects in humans. This has sparked considerable interest in the development of such molecules as novel anti-inflammatory agents and highlighted the necessity to better understand the B-subunit's mode of action. Current theory specifies that the B-subunit mediates its immunomodulatory effects by binding and cross-linking a ubiquitous plasma membrane glycosphingolipid, GM1 ganglioside. The essential role of GM1-interaction was recently challenged by our discovery that a mutant B-subunit (H57A) was unable to modulate the immune system even though it still bound to GM1; suggesting that the B-subunits interact with another receptor (or co-receptor), and that it is this second interaction that directs the immune system to prevent development of autoimmune disease. The primary aims are to characterize the nature of B-subunit interaction with the cell membrane and to identify the co-receptor. This work has the potential to provide a new target for drug discovery and development of immunotherapeutics.Read moreRead less
Interactions Between HIV And Mycobacterial Infections Of Macrophages Mediated By Changes In Gene Expression
Funder
National Health and Medical Research Council
Funding Amount
$119,625.00
Summary
HIV-AIDS and tuberculosis are two of the worlds most important diseases. HIV-AIDS is the fourth leading killing disease worldwide and tuberculosis is the leading opportunistic infection in patients with AIDS particularly in the developing world. Both microbes infect the same cell type, the macrophage, which is widely distributed throughout the body, particularly in lymph nodes and lung. Recent studies in humans have shown that HIV and TB like organisms stimulate each others growth. This study us ....HIV-AIDS and tuberculosis are two of the worlds most important diseases. HIV-AIDS is the fourth leading killing disease worldwide and tuberculosis is the leading opportunistic infection in patients with AIDS particularly in the developing world. Both microbes infect the same cell type, the macrophage, which is widely distributed throughout the body, particularly in lymph nodes and lung. Recent studies in humans have shown that HIV and TB like organisms stimulate each others growth. This study uses the immense power of DNA microarrays, based on the identification of almost all genes by the human genome project, to decipher the interactions between the two microbes. By following up new leads indicated by the microarrays, the way in which the microbes manipulate the macrophage to enhance their own growth and that of the other can be eventually deciphered. This will provide new strategies for future interventions. New drugs are urgently needed for both microbes.Read moreRead less
Identification Of Novel Colonisation Factors In Helicobacter Pylori
Funder
National Health and Medical Research Council
Funding Amount
$336,142.00
Summary
The discovery by Drs Marshall and Warren of the bacterium Helicobacter pylori, and its role in stomach disease, has proven to be one of the major break-throughs of the late 20th century. Indeed, several common ailments of the upper digestive tract that were once thought to be untreatable, or which could only be treated by radical surgery, are now managed through the use of antibiotics and acid-blocking substances. The efficacy of these treatments has, however, been affected by the increasing rat ....The discovery by Drs Marshall and Warren of the bacterium Helicobacter pylori, and its role in stomach disease, has proven to be one of the major break-throughs of the late 20th century. Indeed, several common ailments of the upper digestive tract that were once thought to be untreatable, or which could only be treated by radical surgery, are now managed through the use of antibiotics and acid-blocking substances. The efficacy of these treatments has, however, been affected by the increasing rates of H. pylori resistance to these antibiotics in the general community. Furthermore, the limited choice of antibiotics available for use in anti-H. pylori treatment regimens, and the side-effects associated with several of these compounds, suggest that there is a need to develop new therapies against this bacterial infection. This, however, will necessitate a greater understanding of the mechanisms by which H. pylori is able to colonise and survive in the mucus layer covering the stomach. To address this point, we have used a gene profiling technique to compare gene expression in H. pylori bacteria displaying high and low levels of colonisation in a mouse model. For this, mouse-colonising H. pylori bacteria were attenuated through extensive passaging on culture media in the laboratory. Five genes were identified as being poorly expressed in the attenuated bacteria. These genes are proposed to encode putative H. pylori colonisation factors. The aim of the project is to characterise these factors, and to determine the roles of two of these, which are involved in the production of vitamin B6, in the colonisation of the stomach. This work will contribute to a greater understanding of the factors involved in H. pylori colonisation of the stomach. Amongst the possible public health benefits of this work is the identification of molecular targets for the development of new therapies for the prevention and treatment of H. pylori infection.Read moreRead less
The Role Of The Intracellular Pathogen-recognition Molecule Nod1 In The Host Response To Helicobacter Pylori Infection.
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
The report in 1982 by two Australian clinicians, Drs Marshall and Warren, of a link between a spiral-shaped bacterium, Helicobacter pylori, and stomach disease in humans was to prove one of the ground breaking discoveries of medical research in the last 20-30 years. Despite extensive studies since, including the sequencing of the entire genomes of two different H. pylori isolates, many issues relating to H. pylori disease remain unanswered. For instance, it is still not known why all infected in ....The report in 1982 by two Australian clinicians, Drs Marshall and Warren, of a link between a spiral-shaped bacterium, Helicobacter pylori, and stomach disease in humans was to prove one of the ground breaking discoveries of medical research in the last 20-30 years. Despite extensive studies since, including the sequencing of the entire genomes of two different H. pylori isolates, many issues relating to H. pylori disease remain unanswered. For instance, it is still not known why all infected individuals develop inflammation of the stomach lining, yet only a proportion (15-20%) will go on to develop severe diseases, such as peptic ulcer disease and stomach cancer. Recent work from our groups has identified the mechanism by which H. pylori induces host responses in the cells lining the stomach, the epithelial cell. The interaction of the bacterium with these cells represents its first contact with the host, and sets the scene for the development of immune responses in the stomach. From their position on the outside surfaces of epithelial cells, certain strains of H. pylori are able to deliver a bacterial component into host cells, thus triggering an inflammatory response in the latter. Curiously, a host molecule called Nod1, which is present on the inside of cells and not on the surface, acts as an internal sensor by interpreting the entry of this H. pylori component as a danger signal for the host. The aim of the project will be to characterise the resulting defence mechanisms that are induced by Nod1 in order to prevent the colonisation of the stomach by H. pylori bacteria. It is expected that this work will address questions concerning the role of host immune defence mechanisms in H. pylori infection and stomach disease. Amongst the possible public health benefits of this work will be the development of novel therapies to reduce inflammation in the stomach by blocking Nod1 responses to H. pylori bacterial components.Read moreRead less