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
Asthma is a major health problem for the Australian community. Recent studies have shown increasing numbers of people of all ages are developing asthma. Despite extensive asthma research and the development of new asthma drugs, asthma remains a leading cause of ill- health, especially in children. In many 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. How they do t ....Asthma is a major health problem for the Australian community. Recent studies have shown increasing numbers of people of all ages are developing asthma. Despite extensive asthma research and the development of new asthma drugs, asthma remains a leading cause of ill- health, especially in children. In many 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. How they do this is not completely understood. Asthma causes a unique type of inflammation in the airways, which is present in even mild asthma and can be controlled by medication. Viruses also cause inflammation by infecting the lungs. Viruses can cause severe attacks of asthma even when asthma appears controlled on medication. The ways in which virus infections do this, are not established. By understanding how this happens we may be able to design effective treatment for this problem. Our initial results indicate that virus induced asthma is different to asthma that is triggered by allergens. 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 then evaluate the role of treatment of virus induced asthma. 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
Exposure Of Bronchial Epithelial Cells To Inflammatory Stimuli Impairs Their Innate Immune Response To Rhinovirus.
Funder
National Health and Medical Research Council
Funding Amount
$325,966.00
Summary
Asthma and chronic obstructive pulmonary disease (COPD) are the most common respiratory conditions in Australia, both of these conditions are characterised by acute attacks precipitated by respiratory virus infections. The most common trigger for these acute attacks is the usually innocuous common cold virus, rhinovirus. The reason for this susceptibility remains poorly understood. We have previously shown that the cells lining the airways of asthmatics are more susceptible to infection with rhi ....Asthma and chronic obstructive pulmonary disease (COPD) are the most common respiratory conditions in Australia, both of these conditions are characterised by acute attacks precipitated by respiratory virus infections. The most common trigger for these acute attacks is the usually innocuous common cold virus, rhinovirus. The reason for this susceptibility remains poorly understood. We have previously shown that the cells lining the airways of asthmatics are more susceptible to infection with rhinovirus and fail to react to this infection effectively. We propose to further elucidate this defect and for the first time determine if it is also present in subjects with COPD. We will examine the airway cells of subjects with asthma and COPD and look for evidence of a defective immune response, relating this to the presence of persistent bacterial infection. We will then grow these and infect them with rhinovirus, carefully examining the mechanisms behind this impaired response to infection and then see if we can induce such impairment in these cells with chronic exposure to infection and inflammatory stimuli. Our laboratory is well placed to investigate these problems with an established track record in investigating patients with inflammatory airways disease and virus infection, unparalleled access to sufficient well characterised clinical samples and have demonstrated the ability to study virus epithelial cell interactions. This work will highlight those at risk of developing frequent debilitating exacerbations along with the reasons for this and identify areas to target novel therapeutic interventions.Read moreRead less
In the asthmatic lung structural changes or remodelling occur, which are thought to contribute to the abnormal functioning of the airways. These remodelling events which occur in the asthmatic airway include increased deposition of proteins which form the scaffolding of the airways (the extracellular matrix ECM proteins), and an increased mass of bronchial smooth muscle cells. Many of these critical structural changes are not reversed or prevented with current asthma therapy. Remodelling is an i ....In the asthmatic lung structural changes or remodelling occur, which are thought to contribute to the abnormal functioning of the airways. These remodelling events which occur in the asthmatic airway include increased deposition of proteins which form the scaffolding of the airways (the extracellular matrix ECM proteins), and an increased mass of bronchial smooth muscle cells. Many of these critical structural changes are not reversed or prevented with current asthma therapy. Remodelling is an important process in both the development and progression of asthma. The reason why remodelling occurs in the lungs of people with asthma is not known. It is thought that persistent inflammation drives the remodelling process; however remodelling can perpetuate inflammation, thereby creating a cyclic series of events. Furthermore we have shown that cells from non-asthmatic volunteers which are grown on asthmatic ECM change to become more like cells from asthmatic subjects. Viruses which infect the lungs may play a role in the development of asthma, and in the increased remodelling which is observed. Many common respiratory viruses are capable of infecting lung cells, eg epithelial cells, which evokes an inflammatory response. I will investigate if viral infection can alter the remodelling process, using lung cells isolated from asthmatic and non-asthmatic volunteers. Furthermore, I will assess if current and novel treatments are effective in reducing the remodelling process. We have preliminary evidence that infection of lung epithelial cells with rhinovirus (the common cold virus) alters the amount of ECM deposited by these cells. I hypothesise that this process will be increased in cells from volunteers with asthma compared to non-asthma. As current therapeutics are unlikely to be able to reverse these remodelling events these experiments will enable the development of new therapeutics which can target this important aspect of airway disease.Read moreRead less
RNAi Therapeutic Intervention Of Human Viral Respiratory Disease
Funder
National Health and Medical Research Council
Funding Amount
$584,117.00
Summary
Human metapneumovirus (HMPV), causes clinical disease that is very similar to human respiratory syncytial virus (RSV) and co-circulates with RSV. HMPV is emerging as a major cause of morbidity and life-threatening respiratory tract disease in infants, young children and the elderly worldwide. No treatment is currently available. The objectives of this proposal are to develop novel antiviral drugs that silence the expression of viral genes and to examine protection against the disease.
Mechanism/s Of Disease Caused By Respiratory Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$479,517.00
Summary
A newly discovered respiratory virus, human metapneumovirus (HMPV), causes clinical disease that is very similar to human respiratory syncytial virus (RSV) and co-circulates with RSV. Human RSV is a major cause of morbidity and life-threatening respiratory tract disease in infants and young children worldwide, and is recognised as an important respiratory pathogen in elderly adults and immune compromised patients. The recent isolation of HMPV from children hospitalised with respiratory tract ill ....A newly discovered respiratory virus, human metapneumovirus (HMPV), causes clinical disease that is very similar to human respiratory syncytial virus (RSV) and co-circulates with RSV. Human RSV is a major cause of morbidity and life-threatening respiratory tract disease in infants and young children worldwide, and is recognised as an important respiratory pathogen in elderly adults and immune compromised patients. The recent isolation of HMPV from children hospitalised with respiratory tract illness similar to RSV, but with an unknown etiology, suggests that HMPV may mediate similar clinical pathology. Nothing is currently known about the immune response to HMPV, or the association of these responses with lung disease. The objectives of this proposal are to elucidate the mechanisms of immunity and disease pathogenesis associated with human metapneumovirus (HMPV) and to investigate the use of a novel vaccine to protect against HMPV infection. Once this data is obtained, the study will provide the foundation for further research in the development of vaccines or therapeutic protocols to treat HMPV. It will also provide valuable information for understanding the disease in humans. Also,it is likely that HMPV, like hRSV, may prove to be an agent associated with long-term decreased pulmonary function and airflow limitation perhaps developing to asthma.Read moreRead less
Mechanisms Underlying Acute Changes In Lung Function And Airway Responsiveness Following Respiratory Viral Infections
Funder
National Health and Medical Research Council
Funding Amount
$444,878.00
Summary
This study will investigate the mechanisms responsible for the increased airway responsiveness seen during respiratory viral infections to the common viruses of influenza (flu) and respiratory syncytial virus (RSV). Respiratory viral infections alter lung function and increase airway responsiveness in man. In addition, respiratory viral infections early in life are a risk factor for the subsequent development of asthma. The mechanisms responsible for this are unknown. Both the infecting virus an ....This study will investigate the mechanisms responsible for the increased airway responsiveness seen during respiratory viral infections to the common viruses of influenza (flu) and respiratory syncytial virus (RSV). Respiratory viral infections alter lung function and increase airway responsiveness in man. In addition, respiratory viral infections early in life are a risk factor for the subsequent development of asthma. The mechanisms responsible for this are unknown. Both the infecting virus and host factors, such as age of infection, gender and genetic predisposition, are likely to be important. OUTCOMES and SIGNIFICANCE: These studies will provide a comprehensive assessment of the effects of acute viral respiratory infections on lung function and airway responsiveness using cutting edge techniques developed in our labs. The results will provide new insights into how these infections cause lung disease and may provide clues for new approaches to prevent the adverse effects of these common respiratory viral infections.Read moreRead less
Pneumovirus Infection In Infancy Affects The Development Of Life-long Adaptive Immunity.
Funder
National Health and Medical Research Council
Funding Amount
$408,469.00
Summary
Respiratory syncytial virus is the most important cause of acute lower respiratory tract infection (RTI) in young children worldwide. Hospital admission rates in Western societies for RTIs are around 3% for children younger than 1 year. A vaccine to RSV is not yet available and repeat infections occur thoughout life, suggesting that the immune response does not develop correctly. In this project we are exploring the mechanisms that underpin disease development and promote incomplete immunity.