Viral Infection And Exacerbations Of Asthma During Pregnancy: Characteristics, Mechanisms And Consequences
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
At least 12% of pregnant women in Australia have asthma and more than half of these women will experience an acute attack during pregnancy. This puts the fetus at risk of poor outcomes such as low birth weight or premature birth, which has a significant impact on their health in both the short term and long term. The mechanisms which lead to exacerbations of asthma during pregnancy are unknown, but have implications for the treatment of pregnant women with asthma. In non-pregnant adults, the maj ....At least 12% of pregnant women in Australia have asthma and more than half of these women will experience an acute attack during pregnancy. This puts the fetus at risk of poor outcomes such as low birth weight or premature birth, which has a significant impact on their health in both the short term and long term. The mechanisms which lead to exacerbations of asthma during pregnancy are unknown, but have implications for the treatment of pregnant women with asthma. In non-pregnant adults, the majority of asthma exacerbations are caused by viral infection and it is likely that a similar mechanism operates in pregnant women with asthma. No previous studies have identified the viruses responsible for exacerbations of asthma during pregnancy. We currently have a promising lead in this area, with data showing that one third of pregnant women with asthma have a severe exacerbation of their asthma requiring medical intervention during pregnancy, and a large proportion of these are likely to be due to viral infection. We propose that during pregnancy, pregnant women with asthma are more susceptible to viral infection than pregnant women without asthma. We also suggest that women with asthma will have more severe viral infections during pregnancy, and that these will contribute to the majority of acute asthma attacks during pregnancy. This project will determine the rate of infection among pregnant women with and without asthma and determine the viruses responsible for acute attacks of asthma during pregnancy. The study will also explore the inflammatory mechanisms which predispose women to viral infection. These results will contribute to a greater understanding of the mechanisms leading to exacerbations of asthma during pregnancy and will be used to develop more appropriate asthma monitoring and treatment strategies for pregnant women, which will have health benefits for both mother and baby.Read moreRead less
Immune Cell Interactions And Cell Signalling Pathways Important For Rotavirus Infection
Funder
National Health and Medical Research Council
Funding Amount
$343,812.00
Summary
Rotaviruses are the main cause of severe diarrhoea in Australian children, through infection of the gut cells that absorb food. This project aims to understand the effects of rotaviruses on the functioning and survival of these cells at the molecular level. It will similarly determine the effects of rotavirus infection on the immune cells. These studies will increase understanding of how rotaviruses cause disease, and assist in the development of drugs or improved vaccines against rotavirus.
Hepatitis C virus (HCV), the main cause of of post-transfusion and community -acquired non-A, non-B hepatitis, infects approximately 170 million humans world-wide with some 135,000 infections in Australia alone. HCV is hyper-endemic in intravenous blood users with typical prevalence rates of 60-70%. About 75-80% of infected individuals develop a chronic infection, usually resulting in recurrent, progressively worsening liver damage. Cirrhosis develops in 10-20% of chronic cases while 1-5% of chr ....Hepatitis C virus (HCV), the main cause of of post-transfusion and community -acquired non-A, non-B hepatitis, infects approximately 170 million humans world-wide with some 135,000 infections in Australia alone. HCV is hyper-endemic in intravenous blood users with typical prevalence rates of 60-70%. About 75-80% of infected individuals develop a chronic infection, usually resulting in recurrent, progressively worsening liver damage. Cirrhosis develops in 10-20% of chronic cases while 1-5% of chronic carriers develop liver cancer. Development of an effective vaccine is complicated due to the highly variable nature of the virus. Approved therapies include alpha-interferon and alpha interferon-ribavirin combinations but these treatments induce efficacious responses in only 20-30% of patients and often have severe side-effects. It is assumed that after attachment of HCV to the cell surface, the virus is internalised by the cell and undergoes fusion with a cellular compartment referred to as an endosome. The low pH environment of the endosome is presumed to trigger viral fusion via its cell surface glycoproteins and empties the replication machinery of the virus into the cell. No reliable systems for the propagation of HCV are available thereby limiting studies into the mechanisms of how HCV infects cells and the development of vaccines. Recently a cell surface molecule, CD81, was identified as a possible receptor for the attachment of HCV to susceptible cells. Our aim is to 1) develop model systems for studying HCV entry and fusion and 2) further characterise the interaction of the HCV glycoproteins with CD81 with the goal of obtaining a three-dimersional structure of the interaction . These studies will address the fundamental questions of how HCV enters cells leading new avenues for the design of inhibitors of HCV entry.Read moreRead less
Characteristics And Mechanisms Of Persistent Asthma After Common Cold Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$407,750.00
Summary
Asthma is a major health problem for the Australian community. Recent studies have shown increasing numbers of people of all ages are developing asthma, and despite a fall in asthma deaths, large number of people continue to have severe attacks requiring hospitalisation. In most cases the deterioration in asthma symptoms is related to a cold or flu like illness. Viruses are the leading cause of these infections and are known to make asthma symptoms worse. We have identified how viruses do this b ....Asthma is a major health problem for the Australian community. Recent studies have shown increasing numbers of people of all ages are developing asthma, and despite a fall in asthma deaths, large number of people continue to have severe attacks requiring hospitalisation. In most cases the deterioration in asthma symptoms is related to a cold or flu like illness. Viruses are the leading cause of these infections and are known to make asthma symptoms worse. We have identified how viruses do this by triggering a type of inflammation in the airways. We have also found that after a severe attack of asthma some people do not recover completely. They appear to have persistent problems, and in some cases the virus can still be isolated from the airways. How and why this occurs is not known. We are seeking to understand this problem and describe how it affects people with asthma. We plan to investigate what effect certain viruses have on the lungs of people with asthma by measuring cells and chemicals that are present in sputum. We will use recently developed technologies to accurately see what viruses are infecting these people, and how the immune system is working. This study will shed important light on potential causes of unstable asthma and the role that viral infection plays in this. It may also lead to new opportunities to develop treatments that are more effective in preventing and controlling asthma.Read moreRead less
Mechanisms Of Immune Modulation By Varicella Zoster Virus During Cutaneous Infections
Funder
National Health and Medical Research Council
Funding Amount
$570,446.00
Summary
Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes two skin diseases: chicken pox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease. Shingles aff ....Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes two skin diseases: chicken pox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease. Shingles affects many elderly individuals and a major complication is prolonged severe pain or post-herpetic neuralgia (PHN), which can be severely debilitating and often requires follow-up medical care for months or even years after the initial attack. Despite its significant impact on the community, little is known about how this virus functions and causes disease. This project aims to improve our understanding of how VZV infection of the skin affects the function of specialised skin cells in order to provide novel information for the development of therapies aimed at lessening the impact of VZV disease on the community. This project has three main components: (1) To determine what the differences are in the types of immune cells present in infected skin from chicken pox and shingles sufferers. (2) To assess the impact of VZV infection on the ability of specialised immune cells (called dendritic cells) to function properly (3) To identify which parts of the virus (called genes) code for functions that interfere with the proper function of specialised immune cells (dendritic cells)Read moreRead less
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.
Hepatitis C Virus infects 3% of the world's population causing recurring liver disease, cirrhosis and hepatocellular carcinoma. To infect a liver cell, the viral glycoproteins attach to cell surface molecules wher they are activated to mediate merger of the viral and cellular membranes. This project grant will explore how the viral glycopropteins become activated and obtain essential structural information on the viral glycoproteins. These studies will help us to design antiviral agents.
Structure And Function Of Hepatitis C Virus Glycoproteins
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
Hepatitis C Virus infects approximately 200 million people world-wide and is the major cause of liver transplantation in the Western world. At present there is no vaccine and interferon alpha is the only therapy available and has only limited success in clearing viral infection. HCV is distantly related to flaviviruses eg tick-borne encephaltitis virus and yellow fever virus. All viruses attach to target cells using receptors to initiate the infection process. In the case of HCV, the envelope gl ....Hepatitis C Virus infects approximately 200 million people world-wide and is the major cause of liver transplantation in the Western world. At present there is no vaccine and interferon alpha is the only therapy available and has only limited success in clearing viral infection. HCV is distantly related to flaviviruses eg tick-borne encephaltitis virus and yellow fever virus. All viruses attach to target cells using receptors to initiate the infection process. In the case of HCV, the envelope glycoproteins interact with as yet unknown receptors on the target cell surface resulting in the virus being internalized into endosomes. It is believed that the low pH environment of these endosomes triggers fusion of the viral and cellular membranes. After fusion the genome of the virus is released into target cells and begins the replication process. The actual events intitiating these processes are not understood for HCV but are believed to be mediated using two envelope glycoproteins. In this project we seek to gain a greater understanding of how viral fusion and entry occurs. We have new information regarding the localisation of the two envelope glycoproteins that will now enable us to carefully examine how viral fusion occurs. Using biochemical approaches, we will study their structure and function and examine how this relates to the well understood flavivirus mode of fusion and entry. We will test the functional consequences of altering the structure of the HCV envelope glycoproteins by developing in vitro assays of HCV fusion. Assays for HCV fusion are essential for future studies to identify viral receptors, examine the role of antibody in viral neutralization and can be used to test novel inhibitors of viral fusion and entry.Read moreRead less