Viral And Host Cell Gene Expression During The Establishment And Maintenance Phases Of Human Cytomegalovirus Latency
Funder
National Health and Medical Research Council
Funding Amount
$149,250.00
Summary
Human cytomegalovirus (CMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing CMV disease. Like other herpesviruses, after initial infection CMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body and ....Human cytomegalovirus (CMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing CMV disease. Like other herpesviruses, after initial infection CMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body and no infectious virus is made. However, when conditions are right the virus can awaken (ie reactivate) from its latent state, producing new infectious virus and disease. It is in immunosuppressed individuals such as transplant patients that viral latency and reactivation are of most medical concern, yet viral latency remains very poorly understood. The overall aim of these studies is to provide a much better understanding of how CMV latency is established and maintained, with the ultimate goal of making advances for the design of anti-viral therapies to disrupt these processes. This project has three major components: Firstly, we aim to identify and characterise viral gene expression during the establishment of latency and these findings will have profound implications to our understanding of latency. Secondly, we will examine how human cells are affected when they become latently infected. A new and exciting technology called DNA microarray now makes it possible to examine the expression of many thousands of genes in a single experiment. For the first time, we will be able to determine how the cell changes during the establishment and maintenance phases of latency. Thirdly, we will apply microarray technologies to determine how human cell genes are altered in response to the expression of individual viral genes that are active during the latent phase of infection.Read moreRead less
Mechanisms Of Immune Modulation By Human Cytomegalovirus During The Latent Phase Of Infection
Funder
National Health and Medical Research Council
Funding Amount
$165,500.00
Summary
Human cytomegalovirus (CMV) is a herpesvirus which infects a majority of the population. CMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Bone marrow and solid organ transplant recipients are particularly at risk of developing serious CMV disease. CMV has the remarkable ability to hide in the body in a dormant or latent form for the life of the host. However, when conditions are right the virus can awaken (ie reactivate) from its ....Human cytomegalovirus (CMV) is a herpesvirus which infects a majority of the population. CMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Bone marrow and solid organ transplant recipients are particularly at risk of developing serious CMV disease. CMV has the remarkable ability to hide in the body in a dormant or latent form for the life of the host. However, when conditions are right the virus can awaken (ie reactivate) from its latent state, producing new infectious virus and disease. It is in immunosuppressed individuals such as transplant patients that reactivation from latency is of most medical significance, yet the latent phase of infection remains very poorly understood. We recently reported that during latent infection CMV interfered with the expression of a protein which plays a crucial role in our immune system. This protein is called MHC class II and its proper function is essential for our immune system to fight infections. Thus, we postulated that the ability of CMV to successfully hide in a cell in a latent state is at least partially due to its ability to interfere with the cells ability to properly make MHC class II proteins. This project aims to futher define and characterise the functions of latent CMV that enable it to interfere with our immune system. Firstly, we aim to continue with our studies to determine the mechanism by which latent CMV interferes with MHC class II expression. Secondly, we will seek to determine whether latent CMV interferes with any other important components of our immune system. Thirdly, we will seek to identify the precise viral gene that causes the interference with MHC class II expression. Determining the mechanism of immune system regulation and the viral gene(s) responsible for this interference may lead to the design of gene therapies to lessen the clinical impact of CMV disease in transplant recipients.Read moreRead less
Human Cytomegalovirus Gene Expression And Functions During Latent Infection And Reactivation
Funder
National Health and Medical Research Council
Funding Amount
$789,473.00
Summary
Human cytomegalovirus has the ability to hide in the body in a latent form for the life of the host. However, the virus can awaken (reactivate) from its latent state, producing new infectious virus and disease. It is in immunosuppressed people such as transplant patients that reactivation from latency causes significant morbitity and mortality, yet the latent infection remains very poorly understood. This project will identify and define the functions of viral genes that facilitate latency.
Cell Migration And Granuloma Formation In The Expression Of Protective Immunity Against Tuberculosis In The Lung
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Tuberculosis (TB) remains an enormous problem worldwide and a continuing health problem in Australia. Most TB is not due to disease at the time of infection, but is a reactivation of dormant infection in people who have never eradicated the organisms. This study will investigate, in mice, how TB is initially contained within the lungs and how reactivation occurs. All mice infected with TB control the infection initially. T lymphocytes are activated and T cells and macrophages are recruited to th ....Tuberculosis (TB) remains an enormous problem worldwide and a continuing health problem in Australia. Most TB is not due to disease at the time of infection, but is a reactivation of dormant infection in people who have never eradicated the organisms. This study will investigate, in mice, how TB is initially contained within the lungs and how reactivation occurs. All mice infected with TB control the infection initially. T lymphocytes are activated and T cells and macrophages are recruited to the lung, migrate into lung tissue and surround infected lung macrophages forming granulomas. We have identified mice that progress to TB disease early after infection (early progressor strains) and another strain that progresses later (late progressors). In the early progressors, lymphocytes are not as efficiently recruited to the lung and do not form the tight granulomas seen in late progressor strains. We plan to make a detailed comparison of these two strains looking at differences in cell-membrane molecules and the soluble messenger molecules (cytokines and chemokines) that provide the signals that attract cells to the lung and direct them to surround infected lung macrophages. By comparing events in early and late progressor strains we will find which molecules are required for initial and long-term containment, and which events lead to breakdown of granulomas and reactivation of disease. In addition, we recently showed that one cytokine, tumour necrosis factor (TNF), is essential for cell migration through the lung. By comparing normal mice with mice deficient in TNF we will study the downstream effects regulated by TNF, particularly the chemokine messengers that direct cell movement into granulomas. By identifying the molecules and cells required to control TB we plan to design improved vaccines to prevent TB infection and improved treatments to prevent disease reactivation.Read moreRead less
I am a molecular parasitologist exploring parasitism in blood-feeding human helminths, with a particular focus on the molecular biology of parasite feeding and immune evasion. I am utilizing this information to develop anti-helminth recombinant vaccines a
Analysis Of Viral And Cellular Gene Expression During Human Cytomegalovirus Latent Infection Of Hematopoietic Cells
Funder
National Health and Medical Research Council
Funding Amount
$407,545.00
Summary
Human cytomegalovirus (HCMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing HCMV disease. Like other herpesviruses, after initial infection HCMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body a ....Human cytomegalovirus (HCMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing HCMV disease. Like other herpesviruses, after initial infection HCMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body and no infectious virus is made. However, when conditions are right the virus can awaken (ie reactivate) from its latent state, producing new infectious virus and disease. It is in immunosuppressed individuals such as transplant patients that viral latency and reactivation are of most medical concern, yet viral latency remains very poorly understood. This project has three major components. Firstly, we aim to continue studies which are defining what viral genes are active (ie expressed) during latent infection. Identification of these genes and determination of how they function may have profound implications to our understanding of latency. Secondly, we will examine how human cells are affected when they become latently infected. A new and exciting technology called DNA microarray now makes it possible to examine the expression of many thousands of genes in a single experiment. For the first time, we will be able to determine how the cell changes during latency and reactivation. The study of viral and cellular gene expression during latency may contribute to the development of drugs which interfere with the viruses ability to become latent or reactivate. Thirdly, we have preliminary results which suggest that latent HCMV may actively avoid detection by the immune system. In this project we also aim to determine the mechanism by which the virus interferes with the expression of molecules which are an essential component of our immune system.Read moreRead less
Next Generation Of Medical Devices And Diagnostics
Funder
National Health and Medical Research Council
Funding Amount
$2,738,220.00
Summary
This Investigator Project will deliver innovative technologies that improve patient wellbeing, make significant economic impact and contribute to answering complex biological questions. This will happen via delivering breakthrough technologies to prevent infections and diagnose diseases – two area that currently require substantial technological advances. In addition to helping patients and clinicians, the project will also deliver solid body of new knowledge that is currently missing.
Clinical Impact Of Clonal Pseudomonas Aeruginosa In Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$547,238.00
Summary
In patients with cystic fibrosis (CF), the normal defence mechanisms are compromised by an inherent genetic fault which results in an extremely sticky and dehydrated mucus. The respiratory system is unable to eradicate microbes (infection) from the lungs of patients with CF which begin to multiply and cause infection and inflammation. Recurring infections are treated with multiple courses of antibiotics and frequent hospitalisation and eventually result in premature death. This study focuses on ....In patients with cystic fibrosis (CF), the normal defence mechanisms are compromised by an inherent genetic fault which results in an extremely sticky and dehydrated mucus. The respiratory system is unable to eradicate microbes (infection) from the lungs of patients with CF which begin to multiply and cause infection and inflammation. Recurring infections are treated with multiple courses of antibiotics and frequent hospitalisation and eventually result in premature death. This study focuses on the major bacterial problem, Pseudomonas aeruginosa. Several studies from Australia and the UK, including our own have shown that about 30% to 45% of patients share the same strain of Pseudomonas aeruginosa within a centre. We know that two dominant strains of Pseudomonas aeruginosa are found in CF centres on the eastern board of Australia. This is unexpected as this bacterium is usually acquired from the environment. The emergence of these clonal strains is causing increasing anxiety in the CF community. This study is designed to provide vitally needed information on the clinical implications of being infected by an clonal strain of Pseudomonas aeruginosa and the risk factors for the acquisition of an clonal strain. This new information will provide a rationale basis for the need for changes to infection control policies (including patient segregation), better outcome predictors for patients infected with clonal strain of Pseudomonas aeruginosa.Read moreRead less
Treatment Of Cerebral Palsy - An Experimental Approach
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Cerebral palsy is characterised by disordered movement evident early in life leading to lifelong disability. The motor disorder arises from an abnormality within the white-matter of the brain that is non-progressive and is identifiable soon after birth. In humans and experimental models of fetal infection there is an increase in markers of inflammation. We will use induce ovine fetal infection and white matter injury to examine if anti-inflammatory treatments can prevent fetal brain damage.
Mechanisms Regulating Establishment Of Persistent Herpesvirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$511,446.00
Summary
Herpesviruses are a major cause of disease worldwide and are amongst the most successful human pathogens, with some viruses infecting more than 80% of the world's population. This group of viruses persist and reactivate in hosts and induce immunosuppression.The control of herpesviruses infections thus represents an important clinical goal. Understanding the mechanisms involved in the induction of viral persistence and immunosuppression is a crucial step towards developing better therapies.