Genetic And Phyisological Regulation Of KIR2DL4 Expression
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
Genetic mutations occur frequently but most are deleterious and are lost from the population. Advantageous mutations are selected for and eventually replace the original gene. However, some mutations are advantageous under one set of circumstances and disadvantageous under others. These mutations often reach a high frequency in the population and are maintained along with the original gene. An example of this situation is the mutation in the haemoglobin gene that causes sickle cell anaemia. A si ....Genetic mutations occur frequently but most are deleterious and are lost from the population. Advantageous mutations are selected for and eventually replace the original gene. However, some mutations are advantageous under one set of circumstances and disadvantageous under others. These mutations often reach a high frequency in the population and are maintained along with the original gene. An example of this situation is the mutation in the haemoglobin gene that causes sickle cell anaemia. A single copy of the mutant gene protects against malaria (advantageous) but a double dose of the gene results in sickle cell anaemia, which is fatal. Both the mutant and original gene are maintained in the population as the number of people dying from sickle cell anaemia is less than the number who would die from malaria if the mutant gene did not exist. This phenomenon is known as balancing selection. There are many examples of balancing selection and for each example there is usually a medical condition associated with a double dose of the mutant gene. We have discovered a new example of balancing selection in one of the genes used by the immune system. Very little is known about the function of this gene. In fact the literature abounds with contradictory findings concerning this gene. Our discovery that a mutant gene is present at very high frequency in the population helps explain these contradictory findings and places us in a very strong position to achieve a much better understanding of the function of this gene. We propose to investigate the basic biology of this gene and how it used in the immune system in order to obtain clues as to which medical condition this mutation may be relevant to.Read moreRead less
Role Of NK Receptors In Susceptibility And Resistance To Human Malaria
Funder
National Health and Medical Research Council
Funding Amount
$546,588.00
Summary
Malaria kills 2 million children every year. However, many eventually become resistant to the disease. What causes some kids to die, and how others become resistant, is unknown. We believe that genes for Natural Killer molecules in the immune system can protect people against malaria, but can also over-react in the wrong way and make things worse. We plan to investigate the role of Natural Killer genes in causing disease and also protecting in young children in Papua New Guinea against malaria.
Host Resistance And Protection Against Oral Candidasis
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Candida albicans is an important opportunistic pathogen, that is widely represented in general medical and dental practice, as well as in the hospital environment. Clinical observations indicate that defects in innate immunity predispose patients to disseminated infection, whereas a weakened cell-mediated immune response is commonly associated with chronic oral infections. Animal models of both chronic and acute oral candidiasis have been developed and characterised by the applicants, and these ....Candida albicans is an important opportunistic pathogen, that is widely represented in general medical and dental practice, as well as in the hospital environment. Clinical observations indicate that defects in innate immunity predispose patients to disseminated infection, whereas a weakened cell-mediated immune response is commonly associated with chronic oral infections. Animal models of both chronic and acute oral candidiasis have been developed and characterised by the applicants, and these have clearly implicated T cells in the process of recovery from primary infection. The models will now be used to analyse the effector mechanisms that lead to clearance of the yeast from the oral cavity, with a particular focus on the role of phagocytic cells, and their interaction with T cells. The acute model will be used to identify immunological variables that can act as markers of protection, and the effectiveness of therapeutic manipulations will be evaluated in the chronic model, with the ultimate aim of developing a protective vaccine for human infections.Read moreRead less
Mechanisms Of Virally-induced Immunosuppression: Effects On DC-NK Networks
Funder
National Health and Medical Research Council
Funding Amount
$566,308.00
Summary
Cytomegalovirus (CMV) infection induces immunosuppression that often results in adverse clinical outcomes. Our previous work established that dendritic cells (DC), cells involved in the initiation of immune responses, are a principle target for CMV. This proposal will test the hypothesis that CMV-induced immunosuppression is mediated by viral interference with DC. Understanding the mechanisms involved in the induction of immunosuppression is a crucial step towards developing better therapies.
Determining The Role Of Rel/NF-kB Transcription Factors In CD8 T Cell Homeostasis.
Funder
National Health and Medical Research Council
Funding Amount
$426,500.00
Summary
NF-kB proteins comprise a family of transcription factors that regulate key genes involved in immune responses, inflammation, cell death and proliferation. This family of proteins are potential drug targets for treatment of various diseases. How and when such inhibitors are used in clinical situations depends on understanding how and which cells of the immune system are specifically affected by the absence of NF-kB proteins. In a number of treatment settings intercurrent viral infections occur f ....NF-kB proteins comprise a family of transcription factors that regulate key genes involved in immune responses, inflammation, cell death and proliferation. This family of proteins are potential drug targets for treatment of various diseases. How and when such inhibitors are used in clinical situations depends on understanding how and which cells of the immune system are specifically affected by the absence of NF-kB proteins. In a number of treatment settings intercurrent viral infections occur frequently and therefore there is an even greater need to understand how the immune system may be affected or compromised in response to the primary treatment. This work will provide insights into the cellular and molecular mechanisms affected by the absnece of a particular NF-kB family member (NF-kB1) in CD8 T cells during normal T cell homeostasis and when challenged with viruses. What we learn from our experiments could have important implications for the development of vaccines.Read moreRead less
Viral Immune Evasion From The NK Cell Ly49H Activation Receptor
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Infection with human cytomegalovirus (HCMV) remains a significant health problem for individuals whose immune systems are immunocompromised (transplant patients and AIDS patients) or poorly developed (such as the foetus and newborn children). While drugs are available to treat HCMV infection the emergence of viral drug escape mutants means there is a medical necessity to develop new therapies and vaccines against this agent. As a basis for this it is important to develop a better understand the ....Infection with human cytomegalovirus (HCMV) remains a significant health problem for individuals whose immune systems are immunocompromised (transplant patients and AIDS patients) or poorly developed (such as the foetus and newborn children). While drugs are available to treat HCMV infection the emergence of viral drug escape mutants means there is a medical necessity to develop new therapies and vaccines against this agent. As a basis for this it is important to develop a better understand the host-virus relationship to rationally design appropriate treatments. As HCMV is species specific and does not infect experimental animals, the murine cytomegalovirus (MCMV) in mice is widely used as a model for HCMV disease. MCMV infection is controlled by both innate and adaptive arms of the host's immune response. Natural killer (NK) cells constitute an important frontline defence against MCMV and understanding how they are activated is of importance to harnessing them for anti-viral control measures. Recently we have shown that NK cells are activated via the interaction of an NK cell activation receptor (Ly49H) with a MCMV-encoded ligand (m157). However, we have also found that MCMV can rapidly mutate its m157 gene to evade effective NK cell control and that wild populations of MCMV have foms of m157 that don't bind to Ly49H. Other studies suggest that m157 can bind to inhibitory NK cell receptors, such as Ly49I, and inactivate the NK cell response. This study seeks to understand the dynamics of the m157-Ly49H and m157-Ly49I interactions. As HCMV infection is also regulated at early stages by NK cells, an understanding of how CMV can rapidly mutate its m157 gene to avoid interaction with Ly49H-expressing NK cells has important implications for understanding human disease caused by HCMV, in terms of potential viral escape from NK cell surveillance.Read moreRead less
Role Of DC-NK Cross-talk In Viral Infection: Defining The Critical Molecular Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$519,000.00
Summary
Dendritic cells (DC) are a highly specialized subset of cells involved in activating the immune system in response to infection. Dendritic cells can activate T cells, which then destroy infected or damaged cells. Recent evidence has suggested that activation of natural killer (NK) cells may also be an important function of dendritic cells. NK cells specialize in the removal of damaged cells and have been shown to be particularly important in controlling viral infection and tumour growth and spre ....Dendritic cells (DC) are a highly specialized subset of cells involved in activating the immune system in response to infection. Dendritic cells can activate T cells, which then destroy infected or damaged cells. Recent evidence has suggested that activation of natural killer (NK) cells may also be an important function of dendritic cells. NK cells specialize in the removal of damaged cells and have been shown to be particularly important in controlling viral infection and tumour growth and spread. The central aim of this work is to determine what mechanisms are used by dendritic cells to activate NK cells during viral infection. The well characterized murine cytomegalovirus model (MCMV) will be used to address this question. MCMV is a model for human cytomegalovirus infection (HCMV). HCMV infection usually poses no risk to healthy individuals, however, in people who are immunosuppressed, such as cancer or AIDS patients, HCMV is a significant cause of mortality. The MCMV infection model has provided important insights as to how the immune system controls infection, and the mechanisms utilized by the virus to circumvent these processes. The proposed studies will enhance our understanding of how natural killer cell function is regulated by dendritic cells, and how viruses may interfere with this process. More importantly, the results will provide critical insights into how immunotherapy protocols may be modified to enhance effectiveness.Read moreRead less
Improving Adaptive Anti-viral Responses: A Key To Eliminating Persistent Viral Infection
Funder
National Health and Medical Research Council
Funding Amount
$402,391.00
Summary
Cytomegalovirus (CMV) can cause a persistent infection that can result in adverse clinical outcomes. Our previous work established that suboptimal adaptive immunity is responsible for viral persistence. This proposal will define the defect in adaptive immunity, its causes and how to improve it. The understanding gained from the proposed studies will provide crucial information for the development of improved anti-viral therapies and vaccines.
Perforin is a cytolytic protein found in cytotoxic lymphocytes. It plays an essential role in the destruction of virus- and pathogen- infected cells as well as tumour cells. Perforin deficiency in humans and experimental animals results in the loss of resistance to many viral infections and dramatically increases the chance of spontaneous tumour formation. Whilst perforin was first characterised two decades ago, its mechanisms of action remain unknown. The current Grant Proposal will capitalise ....Perforin is a cytolytic protein found in cytotoxic lymphocytes. It plays an essential role in the destruction of virus- and pathogen- infected cells as well as tumour cells. Perforin deficiency in humans and experimental animals results in the loss of resistance to many viral infections and dramatically increases the chance of spontaneous tumour formation. Whilst perforin was first characterised two decades ago, its mechanisms of action remain unknown. The current Grant Proposal will capitalise on some recent key technological advances in our laboratory that are enabling us to investigate the mechanisms and the regulation of perforin function. Our recent advances in the field put us in a pre-eminent international position to conduct these studies. In broader terms, the proposed studies will have an immediate impact on our understanding of the mechanisms of cytotoxic lymphocyte regulated immune response and on immune homoeostasis in general. It will also improve our understanding of defence mechanisms against various pathogens and will provide more insight into the role of immune system in protection of the organism against cancer.Read moreRead less