Elucidating The Critical Roles Of ILC1, NK Cell And Innate Memory In Immune Protection
Funder
National Health and Medical Research Council
Funding Amount
$657,024.00
Summary
Natural killer cells are innate cells that provide first line defense against infection and cancer. The recent discovery of a novel innate cell population has modified our vision of the early events necessary for immune protection. Understanding the role of these cells is critical as they could represent viable therapeutic targets. We have developed unique mouse models to experimentally target this population to determine how they are generated and their role in combating infection and cancer.
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
The Balance Of Signals Received By NK Cells Is Modulated By Viruses As A Mean Of Immune Escape.
Funder
National Health and Medical Research Council
Funding Amount
$583,175.00
Summary
Cytomegalovirus (CMV) affects about 60% of the population in Australia. Infection is partially controlled by the immune system but CMV is never eliminated and people remain carriers for the rest of their life. Reactivation of CMV in healthy individuals is usually asymptomatic, but it causes severe diseases in people with immune deficiencies. We seek to discover the mechanisms used by CMV to escape immune surveillance, in order to gain insights into the development of improved antiviral therapies
NOD1 Sensing Of H. Pylori Peptidoglycan Promotes Cell Survival And Bacterial Persistence
Funder
National Health and Medical Research Council
Funding Amount
$792,492.00
Summary
The bacterium H. pylori lives in the stomach of half the world’s population and is a major cause of human disease, including peptic ulcers and stomach cancer. This project will investigate how H. pylori is able to manipulate the host immune system by modifying the composition of its outside layer (the cell wall). In so doing, H. pylori causes changes in cells of the stomach lining that allow the bacterium to persist, but that also may predispose the host to cancer.
Identification Of Risk Factors Associated With Exposure To Australian Bat Lyssavirus
Funder
National Health and Medical Research Council
Funding Amount
$230,344.00
Summary
Australia is one of the few countries in the world known to be free of rabies. A dramatic impact on this status occurred in 1996. A flying fox in northern NSW was found to be infected with a rabies-like virus. Within 16 weeks of this discovery the first human case occurred. A further human case has now been reported. The newly discovered virus, named Australian bat lyssavirus (ABL) was found to be closely related to, but distinguishable from, rabies virus. Rabies virus is responsible for thousan ....Australia is one of the few countries in the world known to be free of rabies. A dramatic impact on this status occurred in 1996. A flying fox in northern NSW was found to be infected with a rabies-like virus. Within 16 weeks of this discovery the first human case occurred. A further human case has now been reported. The newly discovered virus, named Australian bat lyssavirus (ABL) was found to be closely related to, but distinguishable from, rabies virus. Rabies virus is responsible for thousands of human infections each year, mainly in Asia and South Asia where it is endemic in urban dogs. In contrast, other rabies-like viruses have caused only a handful of human infections. Although the number of human cases of ABL is likely to remain low, each of the two known cases has aroused a great deal of public anxiety. The natural hosts appear to be various species of bats which collectively have a distribution along the entire northern and eastern coastlines. The number of potential exposures is therefore quite large and state health departments are devoting considerable resources to dealing with public concerns. This project will establish clearly defined risk factors for exposure to ABL and will allow health authorities to better manage expensive and limited vaccine and therapy resources.Read moreRead less
We seek to gain a detailed understanding of how interactions between the West Nile virus proteins and host factors involved in the IFN response determine the outcome of virus infection. Better understanding of the mechanisms employed by this highly pathogenic virus to disable the mammalian host's IFN response will have wider implications for our understanding of other human diseases such as cancer, autoimmunity and provide new avenues for design of efficient antiviral and anticancer therapies.
Toxoplasma Gondii Infection Of Human Retinal Pigment Epithelium
Funder
National Health and Medical Research Council
Funding Amount
$460,668.00
Summary
Ocular toxoplasmosis is a vision-threatening parasitic eye infection that is common in Australia and worldwide. No treatment cures the disease. This work will characterize cellular and molecular events occuring in the eye during an infection, which is an important first step toward the development of more effective treatments for patients with the condition.
Several members of the Flaviviridae family are major pathogens of humans including dengue (DEN), yellow fever (YF), tick-borne encephalitis (TBE), Murray valley encephalitis (MVE), Japanese encephalitis (JE), and hepatitis C virus (HCV). An Australian flavivirus Kunjin (KUN), however, appears to be naturally attenuated and does not cause an overt disease in humans. In contrast, genetically and antigenically closely related to KUN, New York strain of West Nile virus (NY WN) has already caused ~50 ....Several members of the Flaviviridae family are major pathogens of humans including dengue (DEN), yellow fever (YF), tick-borne encephalitis (TBE), Murray valley encephalitis (MVE), Japanese encephalitis (JE), and hepatitis C virus (HCV). An Australian flavivirus Kunjin (KUN), however, appears to be naturally attenuated and does not cause an overt disease in humans. In contrast, genetically and antigenically closely related to KUN, New York strain of West Nile virus (NY WN) has already caused ~500 deaths and over 20,000 registered infections since its emergence in North America in 1999, including 223 deaths and 9122 infections in 2003 alone. Recent studies with DEN indicated that flaviviruses may interfere with early steps of IFN-signalling pathway. The type I Interferon (IFN) response is the first line of defence against viral infections and many viruses have developed different strategies to counteract this response in order to ensure their survival in the infected host. In this grant we seek to exploit our extensive understanding of the molecular biology of KUN virus and the contrasting behaviour of KUN and NY WN viruses to gain an understanding of the role of flavivirus-mediated suppression of host anti-viral IFN response in virus-host relationships and its importance in determining virus virulence.Read moreRead less