Tissue Specific Antigen Presenting Cell Functions During Infection.
Funder
National Health and Medical Research Council
Funding Amount
$555,325.00
Summary
T cell activation is often inefficient following infection or vaccination, resulting in poor control of pathogens. In this grant, we propose to investigate the cellular basis for sub-optimal CD4+ T cell activation following infection. Specifically, we will study the roles of antigen presenting cells in CD4+ T cell activation in an experimental model of visceral leishmaniasis caused by the human protozoan parasite Leishmania donovani.
The Role Of Protein Oxidation And Isomerization Pathways In The Pathogenesis Of Neisseria Meningitidis
Funder
National Health and Medical Research Council
Funding Amount
$264,816.00
Summary
Neisseria meningitidis causes meningococcal disease. It lives on the surface of the nasopharynx and in certain circumstances, can invade into the bloodstream causing sepsis. This is a complicated process, which involves many proteins produced by the bacteria. Many of these proteins contain a special covalent bond, the disulphide bond, which allows them to function properly. We are investigating how these disulphide bonds are put into proteins.
Regulatory Networks Controlling The Interaction Of Neisseria Gonorrhoeae With The Human Host
Funder
National Health and Medical Research Council
Funding Amount
$361,091.00
Summary
What does Neisseria gonorrhoeae switch on when entering a human cell? Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease (STD) gonorrhoea and globally causes approximately 20-60 million new cases per annum (WHO). Gonococcal infection is the leading cause of pelvic inflammatory disease in women and ~ one third of patients will become infertile. Increased levels of resistance to traditional antibiotics have raised concerns for future treatment options. To date no succ ....What does Neisseria gonorrhoeae switch on when entering a human cell? Neisseria gonorrhoeae is the causative agent of the sexually transmitted disease (STD) gonorrhoea and globally causes approximately 20-60 million new cases per annum (WHO). Gonococcal infection is the leading cause of pelvic inflammatory disease in women and ~ one third of patients will become infertile. Increased levels of resistance to traditional antibiotics have raised concerns for future treatment options. To date no successful vaccine strategies have been developed for this organism, primarily because the cell surface proteins elicit limited immunological protection against other strains. To enable the development of innovative approaches to the control of gonococcal infections, we propose to investigate the regulatory networks in gonococci that are important for initial colonization and survival in the human host. We will examine the role of a class of proteins, called sigma factors, that control the expression of a large number of genes in a concerted fashion. The sigma factors themselves do not recognize environmental signals, but their activity is controlled by a complicated array of proteins that are responsive to changing conditions in the bacterial cell. We have for the first time in any bacterial pathogen, identified all of the genes controlled by sigma factors in the obligate human pathogen, Neisseria gonorrhoeae. We have also found that the mechanisms controlling the activity of the sigma factors in this organism are different to those found in other bacterial pathogens. Our aim is to understand the mechanisms that control sigma factors and to gain insight into how N. gonorrhoeae sense and responds to the host cell during infections.Read moreRead less
Parkinson s disease (PD) is a progressively disabling movement disorder afflicting over 25,000 Australians. It is caused by the degeneration of specific nerve cells in the brain that produce certain chemcials and patients suffer from an inability to move fluently (or ultimately at all). At present we do not know what triggers this neurodegeneration. Current symptomatic treatments give sufferers some relief for a period of time by boosting the amount of these depleted chemicals in the brain. Howe ....Parkinson s disease (PD) is a progressively disabling movement disorder afflicting over 25,000 Australians. It is caused by the degeneration of specific nerve cells in the brain that produce certain chemcials and patients suffer from an inability to move fluently (or ultimately at all). At present we do not know what triggers this neurodegeneration. Current symptomatic treatments give sufferers some relief for a period of time by boosting the amount of these depleted chemicals in the brain. However, the underlying cellular degeneration continues unabated until such treatments are no longer effective. It is necessary to determine the reason for the cell loss in the brain in order to develop successful long-term treatments for this disabling disorder. There have been a number of animal models for PD developed. Comparing the type of tissue damage associated with the cell loss in these models shows that signs of brain inflammation occur prior to the loss of nerve cells. This feature consistently occurs regardless of the method used to produce the disease model. However, inflammation has been poorly studied in PD. Part of the present proposal is to analyse the brain tissue from patients with PD in order to document whether inflammation is also a consistent feature in the regions affected by the disease. Other central nervous system disorders in which inflammation is thought to play a pivotal role often have some genetic predisposition to the disorder and there is evidence of an immune response in their blood. We also wish to examine these aspects in patients with PD. Overall, our study will provide the necessary evidence for or against a primary role for inflammation in the disease process causing the ongoing degeneration in PD. If significant indications for a primary role for inflammation are found, treatments specifically targeting inflammation (already available) can be trialled to slow or stop the neurodegeneration.Read moreRead less
The Role Of Fatty Acid Metabolism In Pathogenicity.
Funder
National Health and Medical Research Council
Funding Amount
$540,075.00
Summary
Fungi which infect humans are a major health problem, especially for those with compromised immune systems (eg. AIDS, transplant and cancer patients). Pathogenic fungi must evade the host s immune system whilst deriving nutrients for growth. Some fungi evade the immune system by residing within host cells. This poses significant challenges to growth due to the nutrient poor environment. By understanding how these fungi adapt to growth inside host cells, new avenues for treatment will emerge.
Induction Of Reactive Oxygen Species By Hepatitis C Virus And Its Role In Liver Pathogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$376,320.00
Summary
The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 20-30 years. There is increased scaring of the liver which can result in liver failure and in some individuals liver cancer. Due to the lack of suitable model systems to study HCV infection and disease progression there is no currently available vaccine and treatment options are limited. While the host defense mechanisms to HCV are relatively well studied the role that vira ....The majority of individuals infected with hepatitis C virus (HCV) show a slow progression of liver disease over a period of 20-30 years. There is increased scaring of the liver which can result in liver failure and in some individuals liver cancer. Due to the lack of suitable model systems to study HCV infection and disease progression there is no currently available vaccine and treatment options are limited. While the host defense mechanisms to HCV are relatively well studied the role that viral proteins and viral replication play in the development of liver disease are not well characterized. Previous experiments in the laboratory have shown that one of the hepatitis C virus proteins results in the formation of toxic oxygen molecules known as a reactive oxygen species. This toxic oxygen molecules can have an effect on liver cells that may enhance the progression of the liver disease process in hepatitis C virus infected individuals. The role that these molecules play in liver cells is unknown but experiments are planned in laboratory model systems and in specimens obtained from hepatitis C virus infected individuals to further examine potential mechanisms. This will hopefully lead to the identification of new treatments for hepatitis C virus liver disease. Some patients with hepatitis C will develop liver cancer, however, all the reasons are not known. Using new technology known as microarray, a consequence of the human genome project, we have been able to look at the expression levels of thousands of genes in liver cancer. Experiments are planned to determine if these genes are important in liver cancer and if they can be used as targets for therapy or to more easily diagnose liver cancer.Read moreRead less
Envelope Glycoprotein Determinants Of Pathogenic, Macrophage-tropic HIV-1 And Their Role In HIV-1 Disease Progression
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected 20 thousand people in Australia and 40 million worldwide. In addition to T-cells of the immune system, HIV-1 can also infect cells of the monocyte-macrophage lineage found in blood, brain, lymph node, lungs, bone marrow, skin and brain. HIV-1 strains that can infect these cells are called macrophage-tropic (M-tropic) strains. Infected macrophages are a major source of new HIV-1 produced in the body, and they compl ....Human immunodeficiency virus type 1 (HIV-1) causes AIDS and, to date, has infected 20 thousand people in Australia and 40 million worldwide. In addition to T-cells of the immune system, HIV-1 can also infect cells of the monocyte-macrophage lineage found in blood, brain, lymph node, lungs, bone marrow, skin and brain. HIV-1 strains that can infect these cells are called macrophage-tropic (M-tropic) strains. Infected macrophages are a major source of new HIV-1 produced in the body, and they complicate therapy by the current drugs used to treat HIV-1 infection because infection is often latent (or dormant) and, unlike T-cells, they are long lived and may continue to produce new virus for the duration of their normal life span. HIV-1 virus from patients with advanced disease (i.e. AIDS) can infect macrophages better than virus from patients at early stages of disease (i.e. just after infection, or during the asymptomatic or healthy period). Therefore, the increased ability of HIV-1 to infect macrophages, i.e., enhanced M-tropism, is an important factor contributing to the development of AIDS in people with HIV-1 infection. However, what causes HIV-1 to increase it's ability to infect macrophages and cause AIDS is unknown. This proposal aims to identify features of HIV-1 that are important for enhanced M-tropism and HIV-1 disease progression. We expect to find that the virus gradually changes during the course of infection to forms that can bind to receptor molecules on the cell more tightly, and to forms that need fewer receptors on the cell surface for infection. We believe that these forms of HIV-1 virus are now better able to infect macrophages, which naturally only have small amounts of receptors on their surface, and also can infect and kill T-cells better, leading to AIDS. This study will contribute to a greater understanding of how HIV-1 causes AIDS, which is necessary for the development of new drugs to treat HIV-1 infection.Read moreRead less