Identifying And Characterising The Molecular Determinants Of Fungal Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$315,375.00
Summary
Fungi which infect humans represent one of the fastest growing public health problems. Like bacteria, fungi can pose a serious threat to infected individuals. This is especially true for individuals whose immune system is compromised in any way due to the direct action of another disease such as AIDS, treaments for diseases like cancer or treatment to prevent rejection in organ transplants. The problem is compounded by the lack of safe and effective treament for fungal infections. Many pathogeni ....Fungi which infect humans represent one of the fastest growing public health problems. Like bacteria, fungi can pose a serious threat to infected individuals. This is especially true for individuals whose immune system is compromised in any way due to the direct action of another disease such as AIDS, treaments for diseases like cancer or treatment to prevent rejection in organ transplants. The problem is compounded by the lack of safe and effective treament for fungal infections. Many pathogenic fungi are capable of growing in two very different forms. Usually only one of these forms is pathogenic and causes disease. Therefore, the genes which keep the fungus in the pathogenic form are important factors for infection. By understanding how fungi are capable of infection and avoiding the immune system, good practices and treatments can be development for these life threatening infections.Read moreRead less
Transposable Element Mobility And Chromosomal Rearrangement In The Fungal Pathogen Cryptococcus During Human Infection
Funder
National Health and Medical Research Council
Funding Amount
$322,028.00
Summary
Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals ....Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals has no apparent immune system defect. For patients with AIDS, in the absence of antiretroviral therapy cryptococcal infection is incurable and requires lifelong treatment with antifungal medication to keep the infection in check. During infection, Cryptococcus is under tremendous stress enforced not only by the immune system and the presence of antifungals, but also by the high temperature, nutrient limiting environment encountered in the host. The proposed research will reveal how Cryptococcus evolves in this environment to enable persistence of infection despite medical intervention. I propose that naturally occurring mobile genetic elements present in the Cryptococcus genome cause chromosomal rearrangements during long term infection to produce gene deletions and duplications that facilitate survival. By characterising these changes and the genes associated with them, the research will identify novel genes involved in pathogenesis and will increase our understanding of the infection process. The expected outcome of this project is a detailed understanding of the roles mobile element movement and chromosomal rearrangement play in Cryptococcus during infection, and how these affect genes that contribute to the pathogenic process. The fundamental knowledge gained from this study will facilitate studies designed to combat infections in the clinical setting, provide new drug targets and help foster the development of more effective therapies.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.
Elucidation Of Proteins Expressed By Pathogenic Fungi During Animal Infection
Funder
National Health and Medical Research Council
Funding Amount
$558,267.00
Summary
Fungi cause a diverse range of diseases and are very difficult to treat. This project looks at the proteins that are made by infectious fungi while they are causing disease in animal cells. Proteins made in particularly high abundance may be essential for the fungus to live and grow in animal tissues. By specifically targeting their production, it should be possible to stop the infection without harming the host cell.
Investigating The Interface Between Host Innate Immune Cells And A Fungal Pathogen
Funder
National Health and Medical Research Council
Funding Amount
$578,085.00
Summary
Fungi which infect humans are a major health problem, especially for those with compromised immune systems (eg. AIDS, transplant and cancer patients). These fungi cause disease by evading the immune system whilst deriving nutrients for growth. Some fungi evade the immune system by residing within host cells; a hostile and nutrient poor environment. This project will study a pathway that we have shown is required for growth inside host cells. This knowledge will open new avenues for treatment.
Molecular Mechanisms Of Intracellular Growth, Survival And Pathogenicity
Funder
National Health and Medical Research Council
Funding Amount
$335,816.00
Summary
Fungi which infect humans are a major health problem, especially for those with compromised immune systems (eg. AIDS, transplant and cancer patients). These fungi cause disease by evading the immune system whilst deriving nutrients for growth. Some fungi evade the immune system by residing within host cells; a hostile and nutrient poor environment. This project will study a pathway that we have shown is required for growth inside host cells. This knowledge will open new avenues for treatment.
Cryptococcal Phospholipases: Structure, And Potential Targets For Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$511,650.00
Summary
Mortality and morbidity from invasive fungal infections have increased substantially over the past two decades, especially in immunocompromised patients, such as those with AIDS. Antifungal drugs marketed at present are not very effective or are toxic. There is a need to identify new metabolic and structural targets, some of which are responsible for fungal virulence, as potential areas for development of new drugs. One such virulence factor discovered in our laboratory is an enzyme secreted by ....Mortality and morbidity from invasive fungal infections have increased substantially over the past two decades, especially in immunocompromised patients, such as those with AIDS. Antifungal drugs marketed at present are not very effective or are toxic. There is a need to identify new metabolic and structural targets, some of which are responsible for fungal virulence, as potential areas for development of new drugs. One such virulence factor discovered in our laboratory is an enzyme secreted by the pathogenic fungus, Cryptococcus neoformans, which is acquired by inhalation into the lungs where it can cause lesions, and eventually spreads to other parts of the body, including the brain (median mortality, 17%). This enzyme breaks down cell membranes, aiding invasion into the host lungs and other tissues, and is called phospholipase B (PLB). It is also produced by several other pathogenic fungi, and is different from human phospholipases. In this project we aim to understand how the PLB is constructed, so that we can work out where the cell membrane components bind to it. We will then design drugs which can bind to the PLB enzyme in place of membrane components and in this way block its harmful effects. We will test the effects of such drugs to make sure they do not interfere with human enzyme systems. Inhibitory compounds may also be able to kill the cryptococcal cells, especially if administered together with currently used therapies. Drugs developed to treat Cryptococcus will then be applicable to other systemic fungal infections - a major advance in the treatment of fungal disease, and a saving of some A$60,000 per patient (estimated from a recent U.S. study).Read moreRead less
Regulation Of Secretion Of The Fungal Virulence Determinant, Phospholipase B
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Serious systemic infections due to fungi have increased dramatically in the past few years, especially in people with poorly functioning immune systems. Treatment of these conditions is problematic because the few drugs which are available are not highly effective, and-or cause significant side-effects. Little is understood of how fungi cause disease, and this problem must be addressed if these infections are to be contained. We have discovered that the enzyme, phospholipase B (PLB), is secreted ....Serious systemic infections due to fungi have increased dramatically in the past few years, especially in people with poorly functioning immune systems. Treatment of these conditions is problematic because the few drugs which are available are not highly effective, and-or cause significant side-effects. Little is understood of how fungi cause disease, and this problem must be addressed if these infections are to be contained. We have discovered that the enzyme, phospholipase B (PLB), is secreted by the disease-causing fungus, Cryptococcus neoformans, and that it is important in enabling the fungus to invade the host's cells and spread around the body from the lungs to the brain, where it can cause meningoencephalitis. PLB is also produced by other disease-causing fungi. The mechanism of PLB secretion is completely unknown. In this project we aim to determine the pathways involved in PLB secretion with the intention of exploiting steps unique to pathogenic fungi, for the future design of new anti-fungal drugs.Read moreRead less
The main purpose of this study is to understand how airborne fungi affect asthmatics who are allergic to them. Fungi or moulds release large numbers of spores into the air that are inhaled. In many cases fungal spores outnumber other particles that carry allergen, such as pollens or cat dander, by 100 to 1. This makes fungi the most common potential allergen in the environment. Fungi have been associated with respiratory diseases including fungal sinusitis, asthma, rhinitis, allergic alveolitis ....The main purpose of this study is to understand how airborne fungi affect asthmatics who are allergic to them. Fungi or moulds release large numbers of spores into the air that are inhaled. In many cases fungal spores outnumber other particles that carry allergen, such as pollens or cat dander, by 100 to 1. This makes fungi the most common potential allergen in the environment. Fungi have been associated with respiratory diseases including fungal sinusitis, asthma, rhinitis, allergic alveolitis and sick building syndrome. Largely due to their diversity and complexity, allergenic fungi have not been well studied and the ways in which individuals vary when inhaling spores is not known. Unlike other allergenic particles, it is unlikely that fungal spores release their allergen as soon as they are inhaled because we have shown in earlier in vitro studies that fungi continue to release allergen over time and this is likely to be the case when they are inhaled. Our laboratory has developed two new techniques that allow us to measure how many spores people inhale and whether they are allergic to them. This study will use these tools to detect and identify the important allergenic fungi involved in domestic and outdoor exposure of asthmatics, the degree of contribution to the total allergen load to which subjects are exposed and identify in what conditions fungi are the causal agents in location-specific symptoms. This study will also investigate allergen production of fungi in situ in the human nose, which will have application in allergic sinusitis and asthma amongst other respiratory diseases. We will investigate how readily allergenic spores germinate in the nose and under what conditions they release allergen.Read moreRead less
Invasive fungal infections are a serious, escalating health issue. They cause severe disease with high death rates and are very costly to the health system. Current drugs often have suboptimal efficacy and cause side effects. New drugs are needed urgently. Many fungi, including the AIDS-related pathogen, Cryptococcus neoformans, secrete phospholipase B (Plbp) to facilitate infection. We will identify and investigate the Plbp secretion pathway as a novel anti-fungal drug target.