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 The Natural Killer Complex In The Control Of Murine Malarial Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
Natural Killer (NK )cells are an essential arm of the innate immune system. NK cell function is controlled by a series of cell surface receptors encoded within a defined genetic region named the Natural Killer Complex (NKC). This region appears to be highly polymorphic both in mice and humans. It is known that different mouse strains, which differ in the expression of NKC molecules have distinct ability to mount inflammatory responses during infection. In fact, we have previously shown that the ....Natural Killer (NK )cells are an essential arm of the innate immune system. NK cell function is controlled by a series of cell surface receptors encoded within a defined genetic region named the Natural Killer Complex (NKC). This region appears to be highly polymorphic both in mice and humans. It is known that different mouse strains, which differ in the expression of NKC molecules have distinct ability to mount inflammatory responses during infection. In fact, we have previously shown that the differential expression of NKC molecules in mice accounts for the degree of susceptibility to Plasmodium berghei-mediated cerebral malaria, a syndrome that accurately reproduces malarial disease induced by Plasmodium falciparum in humans and that results from an exacerbated pro-inflammatory response to infection. Since the NKC comprises several genes and multi-gene families, the main objective of this proposal is to identify which molecule-s within this genetic region are responsible for the induction of cerebral malaria pathogenesis. Our preliminary results indicate that an activation receptor named Ly49D, which is only expressed on the surface of NK cells from cerebral malaria-susceptible mice, plays a key role in disease-induction. Activation of Ly49D induces NK cells to secrete large amounts of IFN-gamma, a pro-inflammatory cytokine known to mediate cerebral-malaria pathogenesis. We will characterize the immunological function of Ly49D+ NK cells during P. berghei infection and determine whether these cells are the main source of IFN-gamma production. We will also identify the ligand (from parasite or host origin) responsible for the stimulation of this NKC activation receptor during malaria infection. The identification and characterization of these NKC receptors will provide new insights to explain the immunological basis of malarial pathogenesis and could lead to the development of therapeutical approaches designed to prevent severe malarial disease.Read moreRead less
Autoimmune Polyendocrine Syndrome Type 1 - A Rare Disorder Of Childhood As A Model Of Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$506,943.00
Summary
This project will analyse the mechanisms and causes of diabetes and other autoimmune diseases where the immune system damages particular organs of the body. Diabetes is a national health priority, and autoimmune diseases collectively affect one in every twenty Australians. The project will focus on a recently discovered gene, Autoimmune Regulator (AIRE) that is crucial for protection against autoimmune disease, which Prof Goodnow's team has shown to stop forbidden clones of T lymphocytes in the ....This project will analyse the mechanisms and causes of diabetes and other autoimmune diseases where the immune system damages particular organs of the body. Diabetes is a national health priority, and autoimmune diseases collectively affect one in every twenty Australians. The project will focus on a recently discovered gene, Autoimmune Regulator (AIRE) that is crucial for protection against autoimmune disease, which Prof Goodnow's team has shown to stop forbidden clones of T lymphocytes in the immune system from attacking our own organs. Inherited defects in the AIRE gene cause a devastating illness, Autoimmune Polyendocrine Syndrome 1, and provide an unparalleled insight into mechanisms of common autoimmune diseases such as Type 1 diabetes, thyroid diseases, pernicious anemia, and Addison's disease. By joining forces with Dr H Scott and a multidisciplinary consortium in Europe, Prof Goodnow's team will investigate how the processes controlled by the AIRE gene cooperate with other genes and mechanisms to prevent autoimmune disease. The work will chart the different control systems that normally protect us from autoimmune diseases, and provide a rational basis for developing new ways to treat and prevent autoimmune diseases. The NHMRC funding enables two leading Australian groups at The Australian National University and at the Walter and Eliza Hall Institute to amplify their world-leading individual efforts by leveraging a set of complementary technologies and clinical resources of an interdisciplinary team in Europe. Goodnow's team has already proved the benefit of this type of Australian-European collaboration. Their work discovering the function of the AIRE gene in stopping forbidden T cells depended on a close collaboration with the genetics group in Finland led by Prof Leena Peltonen, whose team had originally discovered the AIRE gene as part of a large European consortium. Scott's team was part of a parallel European-Japanese consortium that discovered the AIRE gene at the same time. The EURAPS project will build on these collaborative discoveries to chart the mechanisms of autoimmune disease and how they can be cured or prevented.The NHMRC funding for the Australian teams is amplified to a multiplier of twenty-fold by European funding for the overall EURAPS project. This represents a strategic investment to ensure Australian health research remains at the forefront of advances in prevention and treatment of chronic diseases.Read moreRead less
I am a viral immunologist studying the requirements for an effective host response to viral infection. I am also investigating the potential for the development of efficacious vaccines to protect against infection and ways of intervening in the disease pr
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
IgA Mediated Activation Of FcalphaRI, An Fc Receptor And A Leukocyte Ig-like Receptor.
Funder
National Health and Medical Research Council
Funding Amount
$535,500.00
Summary
Our immune system exists to seek and destroy infections caused by bacteria and viruses (pathogens) that would grow in us. B cells in the immune system make antibody tags which attach to pathogens marking them for elimination. A special type of antibody is IgA. IgA occurs in two forms, the first is found at mucosal sites, these are membranous passages in the body, such as the lung, the gut and the genital tract. These communicate with the outside and are the major route of pathogen entry into the ....Our immune system exists to seek and destroy infections caused by bacteria and viruses (pathogens) that would grow in us. B cells in the immune system make antibody tags which attach to pathogens marking them for elimination. A special type of antibody is IgA. IgA occurs in two forms, the first is found at mucosal sites, these are membranous passages in the body, such as the lung, the gut and the genital tract. These communicate with the outside and are the major route of pathogen entry into the body. Here IgA forms a rather passive, but pathogen specific, sticky barrier to prevent microbial pathogens attaching to these large surfaces. In an everyday analogy this IgA behaves somewhat like fly-paper. This subdued response is appropriate as we are constantly exposed to micro-organisms living in our gut, or breathed into our lungs, and our immune system would make us ill if it aggressively attacked our innocuous microbial neighbours. The second type of IgA is found in the blood where it attaches to pathogens that have breached the body's barriers. These IgA tags are actively sought by white blood cells whose function is to protect the body from infection by recognising and engulfing the tagged pathogens and destroying them with killer molecules, including bleach. The IgA-Fc receptor is the sensor on the surface of white blood cells which seeks the IgA tags as they attach to pathogens. In order to survive in this hostile environment some of our pathogens, such as Staphylococcus, have their own strategies to make themselves invisible to the immune system. These strategies include cutting up the IgA tags or blocking the sensors for IgA. In this project we will study how IgA tags turn on white blood cells to destroy pathogens. We will also be looking at two Staphylococcal proteins which block up the sensor for IgA tags. Finally we are endeavouring to understand how it is the mucosal type IgA does not activate the white cells nearly as much as the IgA from the blood.Read moreRead less
Biology Of The Novel C-type Lectin Receptor DCL-1 In Innate And Adaptive Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
The innate immune system is the first line of defense in protecting the body from infection. Phagocytic (meaning eating) white blood cells, which include dendritic cells and macrophages are equipped with cell surface proteins These bind the many types of microbes that cause infection, allowing the phagocytes to destroy them (innate immune response). Furthermore, dendritic cells and macrophages have mechanisms to activate additional specific responses (adaptive immune response) mediated by lympho ....The innate immune system is the first line of defense in protecting the body from infection. Phagocytic (meaning eating) white blood cells, which include dendritic cells and macrophages are equipped with cell surface proteins These bind the many types of microbes that cause infection, allowing the phagocytes to destroy them (innate immune response). Furthermore, dendritic cells and macrophages have mechanisms to activate additional specific responses (adaptive immune response) mediated by lymphocytes (T and B cells). We have discovered a cell surface protein, termed DCL-1, which may play a role in uptake of microbes by phagocytes and activation of innate and adaptive immune responses. This project will examine the mechanisms whereby DCL-1 mediates these immune responses. Understanding the mechanism may allow us to exploit DCL-1 for tumor immunotherapy.Read moreRead less
Immunodominance In Vaccinia Virus And Recombinant Vaccinia Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$388,455.00
Summary
When confronted with an invading microbe, the human immune system does not recognise its overall shape. Instead, the microbe is chopped up into tiny fragments, called peptides, and these can be recognised by special cells of the immune system called T cells which orchestrate a response. We have a good understanding of this chopping process and can predict many of these peptides, but this is only part of the story. Not all peptides will be recognized by a T cell. Further, through processes we do ....When confronted with an invading microbe, the human immune system does not recognise its overall shape. Instead, the microbe is chopped up into tiny fragments, called peptides, and these can be recognised by special cells of the immune system called T cells which orchestrate a response. We have a good understanding of this chopping process and can predict many of these peptides, but this is only part of the story. Not all peptides will be recognized by a T cell. Further, through processes we do not understand well, T cells that recognize only a few out of the many peptides will dominate an entire immune response. As a result, immune responses are focused in such a way that they recognize only a tiny portion of an invading microbe. Focusing of immune responses also occurs during immunization with vaccines. Some new, genetically engineered vaccines use a harmless microbe to carry small parts of more dangerous pathogens. The parts chosen will not cause any disease by themselves, so the whole vaccine is safe. Vaccines built in this way are in clinical trials for diseases such as AIDS and malaria, but do not work as well as was hoped. These new vaccines are largely made up of the carrier and the parts of the microbe we wish to immunize against (e.g. a part of the AIDS virus) will be only a small fraction of the whole vaccine. Ideally we would like the immune system to focus on this small part of our choosing, but the few studies done suggest that this is not the case. In this project we will study vaccines that use a carrier called vaccinia virus. We will test to what extent immune responses are focused inappropriately. We will then genetically alter the virus and use new immunisation strategies to try and shift the focus of the immune response so that it targets the right parts of the vaccine. The ultimate aim is to improve vaccines, but in the process we may learn more about how the immune system chooses its targets.Read moreRead less