Defining The Molecular Effectors And Regulators Of Anti-viral Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
In humans, cytomegalovirus infection can cause severe disease and may even be fatal in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. The majority of healthy individuals however can clear the infection with minimal disease. The ability of cytomegalovirus to cause disease is increased in the absence of effective immune responses which would normally clear the virus before illness occur ....In humans, cytomegalovirus infection can cause severe disease and may even be fatal in individuals with immature or compromised immune systems, such as newborns, AIDS patients, transplant recipients and people treated with chemotherapeutic drugs. The majority of healthy individuals however can clear the infection with minimal disease. The ability of cytomegalovirus to cause disease is increased in the absence of effective immune responses which would normally clear the virus before illness occurs. Understanding the role of specific mediators of anti-viral immune responses is therefore of paramount importance in establishing the guidelines for the design of more effective anti-viral therapies. The mouse model of cytomegalovirus infection provides a unique system to dissect the roles of specific components of the immune response during the course of viral infection. Our previous studies have shown that anti-viral immune responses are complex and involve a multitude of players. The central aim of the work in the current proposal is to establish the precise contribution of specific molecular effectors and regulators of anti-viral immune responses and define their relevance during the different stages of viral infection. Hence, the results of these studies will be relevant to understanding the pathogenesis of cytomegalovirus infection in humans and more importantly will provide critical insights into the rational design of improved antiviral drugs and vaccines. Since the molecules and cells under investigation are also known to play a crucial role in immune responses that control tumour growth and transplant survival, the proposed studies will provide valuable insight towards the development of new therapies for pathologies associated not only with cytomegalovirus infection, but also with the conditions named above.Read moreRead less
A T Cell-Specific GR Promoter Determines Responsiveness To Glucocorticoids In Different Immune Compartments
Funder
National Health and Medical Research Council
Funding Amount
$417,500.00
Summary
Synthetic glucocorticoids, such as dexamethasone and prednisolone, are commonly used as potent anti-inflammatory steroid drug during the treatment of major human trauma and cancer. A side-effect of these very high steroid doses is a major down-regulation of the immune system, particularly massive death of important immune cells called T-cells, which can have a major impact on patient recovery and potential mortality. These T cells are particularly sensitive to glucocorticoid-induced cell death a ....Synthetic glucocorticoids, such as dexamethasone and prednisolone, are commonly used as potent anti-inflammatory steroid drug during the treatment of major human trauma and cancer. A side-effect of these very high steroid doses is a major down-regulation of the immune system, particularly massive death of important immune cells called T-cells, which can have a major impact on patient recovery and potential mortality. These T cells are particularly sensitive to glucocorticoid-induced cell death and have very high levels of receptors for these steroids called glucocorticoid receptors (GRs). We have discovered a unique GR gene promoter (designated 1A) that is active in T cells. Very little is known about how this gene promoter is regulated. This promoter may be a useful therapeutic target to block T cell death (caused by steroids) during recovery from injury, infection and cancer. Separation of anti-inflammatory and side-effects such as high T-cell death or blockade of these effects on T cells would have a major impact on patient immune status and recovery, and reduce the incidence of debilitating side-effects. Therapeutic down-regulation of this T cell-specific GR gene promoter could lead to targeted blockade of steroid-induced T cell death and help maintain a strong immune system. This application brings together a unique team of investigators (CIs) that have a strong history of collaboration in this area with recent publications in very high ranking international journals. The CIs bring a multi-disciplined approach combining endocrinology, molecular biology and cellular immunology to determine the underlying mechanisms of steroid actions and their effects on immune function. Both Dr Cole (CIA) and Dr Godfrey (CIB) have excellent track records in this area.Read moreRead less