THE ROLE OF CELL SURFACE GLYCOSAMINOGLYCANS IN FLAVIVIRUS BIOLOGY: VIRUS ENTRY, TROPISM, VIRULENCE, AND ANTIVIRALS
Funder
National Health and Medical Research Council
Funding Amount
$493,764.00
Summary
The flaviviruses are a group of viruses mostly transmitted by the bite of infected mosquitoes or ticks to vertebrate hosts. They have a world-wide distribution and many flaviviruses are important human and veterinary pathogens. Dengue virus is the most important flavivirus in terms of disease frequency, causing >50 million cases of dengue fever, annually, in tropical and subtropical countries. It has been estimated that 2.5 billion people are at risk of dengue virus infection. Japanese enceph ....The flaviviruses are a group of viruses mostly transmitted by the bite of infected mosquitoes or ticks to vertebrate hosts. They have a world-wide distribution and many flaviviruses are important human and veterinary pathogens. Dengue virus is the most important flavivirus in terms of disease frequency, causing >50 million cases of dengue fever, annually, in tropical and subtropical countries. It has been estimated that 2.5 billion people are at risk of dengue virus infection. Japanese encephalitis virus is the most important causative agent of viral encephalitis in humans; >35,000 cases of Japanese encephalitis occur annually, with 30-50% mortality and frequent life-long neurological impairment among survivors. Murray Valley encephalitis virus is endemic in northern Australia where it gives rise, in most years, to a small number of human cases of sometimes fatal encephalitis. Dengue, Japanese encephalitis, and Murray Valley encephalitis viruses are a threat to human health in Australia. There is wide-spread speculation that climate change will affect the pattern of transmission of vector-borne pathogens; accordingly , the population at risk of flavivirus infection in Australia (and world-wide) may dramatically increase in future years. This project investigates the role of sulfated sugar molecules present abundantly on cellular surfaces in the biology of flaviviruses. It will address how the binding ability of medically important flaviviruses to these sulfated sugars impacts on the efficiency of virus entry into diverse cell types and, in turn, on the virus ability to cause disease. Ultimately, we aim to exploit the affinity of flavivirus particles to the sulfated sugar molecules on cellular surfaces; we will select synthetic mimetics of these sulfated sugars that block virus attachment to cells, and thus may identify antiviral compounds that may find application as therapeutic agents against flaviviral disease.Read moreRead less
Viral Factors Contributing To Flavivirus-induced Cell Death And Pathogenicity
Funder
National Health and Medical Research Council
Funding Amount
$612,885.00
Summary
West Nile virus is a mosquito-transmitted pathogen that causes severe and fatal neurological disease in humans. There are currently no effective treatments or vaccines for this disease. In this project, we will investigate how West Nile virus and other viruses of the same group use a novel translational regulatory mechanism to modulate the host antiviral response and facilitate viral pathogenicity. This will provide valuable information for the development of effective treatments against this me ....West Nile virus is a mosquito-transmitted pathogen that causes severe and fatal neurological disease in humans. There are currently no effective treatments or vaccines for this disease. In this project, we will investigate how West Nile virus and other viruses of the same group use a novel translational regulatory mechanism to modulate the host antiviral response and facilitate viral pathogenicity. This will provide valuable information for the development of effective treatments against this medically important group of viral pathogens.Read moreRead less
The Role Of Subgenomic Non-coding Viral RNA In Flavivirus Pathogenicity
Funder
National Health and Medical Research Council
Funding Amount
$555,325.00
Summary
Flaviviruses are transmitted by insects and pose a serious health threat to the Australian population. They can cause fever syndromes, encephalitis and death. We aim at better understanding of how these viruses cause disease. We are particularly interested in elucidating the role of small non-coding nucleic acid produced by flaviviruses in the viral pathogenicity. Ultimately, this deeper understanding should lead to the development of effective vaccines and antiviral therapies.
Japanese Encephalitis Virus In Australasia: Molecular Studies Of Isolates And Consequences Of Immunisation.
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Japanese encephalitis (JE) virus is a mosquito-transmitted virus of Asia. Infection causes clinical disease in about 1 in 50 people infected, and of these, about 25% will die from a fatal encephalitis (inflammation of the brain), and a further 50% will have lifelong severe disabilities. There are over 50,000 cases annually in Asia, with about 12,000 fatalities.The virus normally circulates between mosquitoes and water birds and between mosquitoes and pigs. The World Health Organization has recog ....Japanese encephalitis (JE) virus is a mosquito-transmitted virus of Asia. Infection causes clinical disease in about 1 in 50 people infected, and of these, about 25% will die from a fatal encephalitis (inflammation of the brain), and a further 50% will have lifelong severe disabilities. There are over 50,000 cases annually in Asia, with about 12,000 fatalities.The virus normally circulates between mosquitoes and water birds and between mosquitoes and pigs. The World Health Organization has recognised JE as one of the most important mosquito-borne viruses because of its propensity to spread and to colonise new areas. The virus first appeared in northern Australia in the Torres Strait in 1995, causing three clinical cases of whom 2 died, and returned again in 1998, with a further case in the Torres Strait and the first case to occur on mainland Australia in Cape York. Both of these patients recovered. The virus returned again to the Torres Strait in 2000, but so far without causing human disease. We have shown that the virus is established in Papua New Guinea (PNG), where it is spreading rapidly, and our results suggest that PNG was the source of the virus causing the outbreaks in 1995 and 1998. It is believed that JE virus will almost certainly become established in Australia within the next few years. The aims of this project are to explore the consequences of JE becoming established and specifically: (a) the use of inactivated JE vaccine to protect at-risk populations and whether the vaccine will provide sufficient protection or whether it will lead to enhanced infection with indigenous flaviviruses such as Murray Valley encephalitis virus; and (b) the possibility of emergence of genetic variants with increased transmissibility, virulence, and altered neutralisation epitopes.Read moreRead less
Mechanisms Underlying Brain Metabolic Changes In Cerebral Malaria.
Funder
National Health and Medical Research Council
Funding Amount
$334,061.00
Summary
About 2 million people die each year from complications of malaria infection. The most common form of these fatal complications is called cerebral malaria. For reasons that are not fully understood, the brain of the patient becomes affected. Early symptoms are behavioural changes, progressing to coma. About 20% of people who enter coma with malaria infection die and the remainder recover, sometimes with slight neurological impairment. During the cerebral malaria attack, the way that the brain ha ....About 2 million people die each year from complications of malaria infection. The most common form of these fatal complications is called cerebral malaria. For reasons that are not fully understood, the brain of the patient becomes affected. Early symptoms are behavioural changes, progressing to coma. About 20% of people who enter coma with malaria infection die and the remainder recover, sometimes with slight neurological impairment. During the cerebral malaria attack, the way that the brain handles sugar, in order to make the energy needed for brain function, is changed. It adopts a pattern rather like a brain that has been starved of oxygen, though whether this actually occurs is not clear. An alternative idea is that this change in brain biochemistry is caused by cytokines. These are protein molecules produced by the immune system as part of the attack on the malaria parasite. Unfortunately, in excess it is known that some of them, particularly the one called tumour necrosis factor, can have deleterious effects on the host (in this case, human beings). Using an experimental model in mice, we will find out which of the two possibilities (lack of oxygen, over-stimulation by cytokines) is responsible for the biochemical changes in the brain in cerebral malaria. This is important because the brain is very susceptible to changes in the pathways that produce the energy needed for it to function properly. From this work we hope to find out better ways of treating cerebral malaria.Read moreRead less
Japanese Encephalitis Virus In Northern Australia And Papua New Guinea:its Ecology And Risk To Australia.
Funder
National Health and Medical Research Council
Funding Amount
$292,045.00
Summary
Japanese encephalitis (JE) virus is a mosquito-transmitted virus of Asia. Infection causes clinical disease in about 1 in 50 people infected, and of these, about 25% will die from a fatal encephalitis (inflammation of the brain), and a further 50% will have lifelong severe disabilities. There are over 50,000 cases annually in Asia, with about 12,000 fatalities. However, many more cases may go unrecognised. The virus normally circulates between mosquitoes and water birds and between mosquitoes an ....Japanese encephalitis (JE) virus is a mosquito-transmitted virus of Asia. Infection causes clinical disease in about 1 in 50 people infected, and of these, about 25% will die from a fatal encephalitis (inflammation of the brain), and a further 50% will have lifelong severe disabilities. There are over 50,000 cases annually in Asia, with about 12,000 fatalities. However, many more cases may go unrecognised. The virus normally circulates between mosquitoes and water birds and between mosquitoes and pigs. The World Health Organization has recognised JE as one of the most important mosquito-borne viruses because of its propensity to spread and to colonise new areas. The virus first appeared in the Torres Strait of northern Australia in 1995, causing three clinical cases of whom 2 died. This was unexpected as the nearest known focus of virus activity was in Bali, over 3000km away. The virus returned again in 1998, with a further case in the Torres Strait and the first case to occur on mainland Australia in Cape York. Both of these patients recovered. We have shown that the virus is established in Papua New Guinea (PNG), where it is spreading rapidly, and our results suggest that PNG was the source of the virus causing the outbreaks in 1995 and 1998. This project is aimed at finding out more about JE virus in PNG, particularly as it relates to spread into northern Australia. The project also seeks to investigate the potential mosquito and animal hosts in Australia that might be involved if the virus becomes established in our wildlife in Cape York. Australia is already known to have suitable mosquito vector species and suitable animal hosts in water birds and feral pigs, but the ecology is not yet understood. Thus the overall aim is to provide information on which a sound risk assessment can be based.Read moreRead less
Roles Of CD8-positive T Cells And Chemokines In Cerebral Malaria.
Funder
National Health and Medical Research Council
Funding Amount
$392,545.00
Summary
About 2 million people die each year from complications of malaria infection. The most common form of these fatal complications is called cerebral malaria. For reasons that are not fully understood, the brain of the patient becomes affected. Early after infection there are behavioural changes, progressing to coma. About 20% of people who enter coma with malaria infection, and are treated with anti-malarial drugs, die and the remainder recover, sometimes with slight neurological impairment. One t ....About 2 million people die each year from complications of malaria infection. The most common form of these fatal complications is called cerebral malaria. For reasons that are not fully understood, the brain of the patient becomes affected. Early after infection there are behavioural changes, progressing to coma. About 20% of people who enter coma with malaria infection, and are treated with anti-malarial drugs, die and the remainder recover, sometimes with slight neurological impairment. One theory to explain cerebral malaria is that is caused by the body's own immunological response against the parasite. Using an experimental model in mice, we will find out whether the immune system cells called CD8-positive T lymphocytes are important in causing the brain complications. We also will find out whether messenger molecules called chemokines are important. From this work we hope to discover better ways of treating cerebral malaria.Read moreRead less