A Functional Interaction Between Domains Of The Flavivirus NS5 Protein Presents A New Target For Antiviral Therapy
Funder
National Health and Medical Research Council
Funding Amount
$502,891.00
Summary
Mosquito-transmitted flaviviruses such as dengue, yellow fever, Japanese encephalitis and West Nile infect hundreds of millions of people and cause debilitating and fatal diseases. Developing anti-viral treatments against these diseases is a high priority. Our strategy is to develop small molecules that can bind to specific sites on viral proteins and prevent the virus from replicating and causing disease.
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
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.
Studies On The Flavivirus Nonstructural Proteins And Untranslated Regions Of The Genome Involved In Virus Replication
Funder
National Health and Medical Research Council
Funding Amount
$244,277.00
Summary
Flaviviruses cause potentially fatal diseases of global importance such as yellow fever, Japanese encephalitis (JE) and dengue haemorrhagic fever. Flavivirus disease is also important in Australia with recurrent outbreaks of dengue fever, Australian encephalitis and more recently JE in the northern regions of the continent. Effective vaccines are only available to yellow fever and JE and tick-borne encephalitis and are either live or killed preparations which are potentially hazardous and costly ....Flaviviruses cause potentially fatal diseases of global importance such as yellow fever, Japanese encephalitis (JE) and dengue haemorrhagic fever. Flavivirus disease is also important in Australia with recurrent outbreaks of dengue fever, Australian encephalitis and more recently JE in the northern regions of the continent. Effective vaccines are only available to yellow fever and JE and tick-borne encephalitis and are either live or killed preparations which are potentially hazardous and costly to produce. There are no therapeutic agents (antivirals) available against flavivirus diseases. To produce safe and cost effective vaccines against flaviviruses and to identify targets for antiviral agents, a more complete understanding of how these viruses replicate in the cell and cause disease is required. This investigation aims to define specific aspects of the flavivirus life cycle that are currently unknown.Read moreRead less
Virulence Determinants Of Encephalitic Flaviviruses
Funder
National Health and Medical Research Council
Funding Amount
$455,670.00
Summary
Murray Valley encephalitis, Japanese enecephaltis virus and West Nile virus are mosquito transmitted pathogens that cause severe and fatal neurological diseases in man and animals. Currenly, it is not clear why these viruses produce such severe diseases and therefore they are difficult to treat and prevent. In this project we will indentify the components of the viruses that allow them to invade the central nervous sytem and cause neurological symptoms. This will provide valuable information on ....Murray Valley encephalitis, Japanese enecephaltis virus and West Nile virus are mosquito transmitted pathogens that cause severe and fatal neurological diseases in man and animals. Currenly, it is not clear why these viruses produce such severe diseases and therefore they are difficult to treat and prevent. In this project we will indentify the components of the viruses that allow them to invade the central nervous sytem and cause neurological symptoms. This will provide valuable information on critical elements of these pathogenic viruses that contribute to their virulence and will identify new candidate vaccines for prevention of the encephalitic diseases they cause.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
A Study Of The Molecular Pathogenesis Of Murray Valley Encephalitis Virus In Mice Using Infectious Clone-derived Virus
Funder
National Health and Medical Research Council
Funding Amount
$194,595.00
Summary
The significance of this project derives primarily from the public health problem posed by epidemics of Murray Valley encephalitis in Australia and, more importantly, by the very much larger and more frequent epidemics of Japanese encephalitis in southeast Asia. Reported case fatality rates of Murray Valley encephalitis and of Japanese encephalitis range from 20 to 40%. Rates of neurological sequelae (motor deficits, mental retardation, convulsions, memory loss) are high among survivors and impo ....The significance of this project derives primarily from the public health problem posed by epidemics of Murray Valley encephalitis in Australia and, more importantly, by the very much larger and more frequent epidemics of Japanese encephalitis in southeast Asia. Reported case fatality rates of Murray Valley encephalitis and of Japanese encephalitis range from 20 to 40%. Rates of neurological sequelae (motor deficits, mental retardation, convulsions, memory loss) are high among survivors and impose a considerable burden on affected individuals and on community health and rehabilitation services. Currently there are no effective treatments, other than supportive measures, available for acute flavivirus encephalitis. The research outlined in this grant application is designed to understand the complex interaction between a pathogenic virus and it's mammalian host at the molecular, cellular and whole animal level. To achieve this aim, we have developed an infectious cDNA clone of Murray Valley encephalitis virus, allowing us to create genetically defined attenuated viruses containing single or limited amino acid differences from the virulent wild-type virus. This research will allow us to achieve a comprehensive understanding of how single or limited nucleotide changes in the genomes of laboratory-derived mutants result in attenuation of virulence in a mammalian host . This research has important implications for the development of genetically defined, live-attenuated flavivirus vaccines engineered from infectious cDNA clones. We have recently shown that the pathogenesis of Murray Valley encephalitis in mice results, in part, from host inflammatory responses. Thus, we plan to rigorously analyze the inflammatory responses to MVE infection in mice and to assess the ability of several anti-inflammatory agents to alleviate the clinical manifestations of acute Murray Valley encephalitis or it's neurological sequelae in mice.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.