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
The Effect Of Innate Immune Responses On The Induction Of Protective Immunity In Murine Typhoid Fever
Funder
National Health and Medical Research Council
Funding Amount
$136,500.00
Summary
Salmonella are important pathogens of humans causing diseases ranging from gastroenteritis, typhoid fever to arthritis. Like most if not all infections, the early interaction between the host and the bacterium is characterised by very non-specific symptoms. These non-specific symptoms arise because the so-called innate immune system is activated by the infection. The purpose of this grant is to establish whether these non-specific symptoms, caused by the release of immunological homrones called ....Salmonella are important pathogens of humans causing diseases ranging from gastroenteritis, typhoid fever to arthritis. Like most if not all infections, the early interaction between the host and the bacterium is characterised by very non-specific symptoms. These non-specific symptoms arise because the so-called innate immune system is activated by the infection. The purpose of this grant is to establish whether these non-specific symptoms, caused by the release of immunological homrones called cytokines, are essential to the development of an effective immune response which can protect against subsequent re-infection. This study has important implications for vaccines, of our understanding of how bacteria cause disease, and the role-capacity of the innate immune system in the development of immunity.Read moreRead less
Host Resistance And Protection Against Oral Candidasis
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Candida albicans is an important opportunistic pathogen, that is widely represented in general medical and dental practice, as well as in the hospital environment. Clinical observations indicate that defects in innate immunity predispose patients to disseminated infection, whereas a weakened cell-mediated immune response is commonly associated with chronic oral infections. Animal models of both chronic and acute oral candidiasis have been developed and characterised by the applicants, and these ....Candida albicans is an important opportunistic pathogen, that is widely represented in general medical and dental practice, as well as in the hospital environment. Clinical observations indicate that defects in innate immunity predispose patients to disseminated infection, whereas a weakened cell-mediated immune response is commonly associated with chronic oral infections. Animal models of both chronic and acute oral candidiasis have been developed and characterised by the applicants, and these have clearly implicated T cells in the process of recovery from primary infection. The models will now be used to analyse the effector mechanisms that lead to clearance of the yeast from the oral cavity, with a particular focus on the role of phagocytic cells, and their interaction with T cells. The acute model will be used to identify immunological variables that can act as markers of protection, and the effectiveness of therapeutic manipulations will be evaluated in the chronic model, with the ultimate aim of developing a protective vaccine for human infections.Read moreRead less
Understanding The Host Pathogen Relationships Of Hendra Virus In Bats, Horses And Humans
Funder
National Health and Medical Research Council
Funding Amount
$648,339.00
Summary
We will examine why bats can be infected with Hendra Virus with no apparent symptoms, yet the virus causes severe disease in other mammals including humans. We will examine the innate immune response towards the virus in the natural host (fruit bats), horses and humans. In addition to the innate immune response we will also examine the adaptive immune response in bats and humans. We hope this information can be used to design new drugs or vaccines to Hendra Virus.
A vaccine to prevent AIDS is urgently needed. The European Union recently awarded over 20 million euros to a European consortium, called EAVI2020, to advance multiple HIV vaccines into human testing. Five Australian HIV vaccine experts are named investigators on this award to provide advanced laboratory analyses and intellectual input into the 5 year program if this NHMRC-EU Collaborative Research Grant is successful.
Characterisation Of Cell-mediated Immune Responses In Burkholderia Pseudomallei Infection
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
The bacterium Burkholderia pseudomallei, causes a life threatening condition known as melioidosis. Melioidosis is emerging as an important infectious disease in tropical regions of Australia and South East Asia. Death rates following acute disease are extremely high. Despite the importance of B. pseudomallei in tropical public health, very little is known regarding how the body's defence mechanisms prevent the spread of infection. The wide distribution of melioidosis in tropical Australia and ot ....The bacterium Burkholderia pseudomallei, causes a life threatening condition known as melioidosis. Melioidosis is emerging as an important infectious disease in tropical regions of Australia and South East Asia. Death rates following acute disease are extremely high. Despite the importance of B. pseudomallei in tropical public health, very little is known regarding how the body's defence mechanisms prevent the spread of infection. The wide distribution of melioidosis in tropical Australia and other parts of the world, and the lack of basic scientific information regarding this disease, has prompted this study. The bacterium lives within the body's cells and therefore does not respond well to standard antibiotic treatment. Although some of the basic immune mechanisms have been identified, how protection to the organism develops remains unclear. In this project we will investigate the effect of B. pseudomallei on immune cells or lymphocytes. This study will determine the patients' immune responses to the bacteria causing the disease. Our research team has already successfully carried out work on several different aspects of melioidosis. The characterisation of the basic immune function determined in the proposed study will provide the scientific basis for improvement in treatment and the development of possible preventive strategies against melioidosis.Read moreRead less
Wheat Proteins, The Duodenal Microbiome And Immune Activation In The Aetiopathogenesis Of Non-coeliac Gluten Sensitivity And Functional Dyspepsia
Funder
National Health and Medical Research Council
Funding Amount
$1,997,150.00
Summary
Functional dyspepsia, characterised by troublesome pain in the upper abdomen, or an inability to finish a regular sized meal, is common, affecting up to 15% of Australians. There are no effective treatments. This project will evaluate the role of diet, in particular wheat, as a driver of the subtle inflammation and disturbances in the microbiome seen in the small intestine of functional dyspepsia patients, and test whether a gluten or wheat free diet is an effective treatment option.
I am a Clinical Immunologist, Immunopathologist, clinical researcher and laboratory scientist exploring the interactions between T cell and viral infections. My area of particular interest is the mechanisms by which HIV infection subverts effective T cel