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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.
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.
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
I am a molecular virologist studying the events of virus replication and virus-host interactions with the ultimate goal to understand the mechanisms determining viral pathogenesis and develop safe and effective vaccines.
Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue. Hepatitis C virus is a member of the same virus family. Using Australian flavivirus Kunjin as a model and advanced techniques in molecular biology, biochemistry and electron micriscopy, the research at SASVRC has established international leadership in the area of flavivirus RNA replication and ultrastructure of virus-infected cells. The objectives of this application are to advance further our u ....Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue. Hepatitis C virus is a member of the same virus family. Using Australian flavivirus Kunjin as a model and advanced techniques in molecular biology, biochemistry and electron micriscopy, the research at SASVRC has established international leadership in the area of flavivirus RNA replication and ultrastructure of virus-infected cells. The objectives of this application are to advance further our understanding of how the flavivirus RNA replication complex synthesizes RNA and how this RNA is specifically packaged to produce infectious virus. To achieve these goals we will employ state-of-the-art molecular biology techniques based on manipulations with infectious complementary DNA copy of Kunjin virus RNA. The intimate understanding of these mechanisms in flavivirus replication should facilitate the design of efficient antiviral drugs by specifically targeting unique events in RNA replication and-or packaging. This may assist in the development of antiviral drugs for treatment of infections caused by other higly pathogenic flaviviruses in Australia, such as dengue, Japanese encephalitis and Murray Valley encephalitis, and in the rest of the wirld such as New York strain of West Nile virus as well as the related heptitis C virus. Understanding the mechanisms of Kunjin virus replication and assembly will also aid in the further development of this virus as a safe vaccine vector against other viruses, e.g. HIV, and diseases such as cancer.Read moreRead less
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.
Coordinated Cleavages In The Flavivirus Structural Polyprotein: Role In Virus Assembly And Host-pathogen Interaction
Funder
National Health and Medical Research Council
Funding Amount
$285,000.00
Summary
Flaviviruses are important human pathogens responsible for epidemics of hemorrhagic fever or encephalitis, world-wide. This project aims to investigate unique aspects in the biology of the flaviviruses with wider cell biological and immunological implications. First, we propose to test a mechanism important for the efficient assembly of virus particles. An understanding of this stage of the virus life-cycle will benefit research applying recombinant DNA technology in order to produce replication ....Flaviviruses are important human pathogens responsible for epidemics of hemorrhagic fever or encephalitis, world-wide. This project aims to investigate unique aspects in the biology of the flaviviruses with wider cell biological and immunological implications. First, we propose to test a mechanism important for the efficient assembly of virus particles. An understanding of this stage of the virus life-cycle will benefit research applying recombinant DNA technology in order to produce replication-incompetent viruses for use in vaccination and gene delivery. Second, we have recently discovered a mechanism for immune-modulation, so far unique to the flaviviruses, which interferes with the immune response important in the destruction of virus-infected cells. This project aims to identify the viral gene products responsible for this phenomenon.Read moreRead less
Molecular Analyses Of Flavivirus RNA Replication, Encapsidation, And Complementation
Funder
National Health and Medical Research Council
Funding Amount
$602,545.00
Summary
Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue. Hepatitis C virus is a member of the same virus family. Using Australian flavivirus Kunjin as a model and advanced techniques in molecular biology, biochemistry and electron micriscopy, the Flavivirus Research Unit at SASVRC has established itself as an international leader in the area of flavivirus RNA replication and ultrastructure of virus-infected cells. The objectives of this application are ....Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue. Hepatitis C virus is a member of the same virus family. Using Australian flavivirus Kunjin as a model and advanced techniques in molecular biology, biochemistry and electron micriscopy, the Flavivirus Research Unit at SASVRC has established itself as an international leader in the area of flavivirus RNA replication and ultrastructure of virus-infected cells. The objectives of this application are to advance further our understanding of how the flavivirus RNA replication complex is assembled, how it synthesizes RNA and how this RNA is specifically packaged to produce infectious virus. To achieve these goals we will employ state-of-the-art molecular biology techniques based on manipulations with infectious complementary DNA copy of Kunjin virus RNA. The intimate understanding of these mechanisms in flavivirus replication should facilitate the design of efficient antiviral drugs by specifically targeting unique events in RNA replication and-or packaging. This may assist in the development of antiviral drugs for treatment of infections caused by other higly pathogenic flaviviruses in Australia, such as dengue, Japanese encephalitis and Murray Valley encephalitis, as well as of the related heptitis C virus.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
Flavivirus Replication - Biogenesis, Ultrastructure And Roles Of Induced Membranes
Funder
National Health and Medical Research Council
Funding Amount
$334,880.00
Summary
Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue, and hepatitis C virus is a member of the same virus family. During virus multiplication in cells, new membrane structures are induced and these represent regions where the replication events occur. Using Kunjin virus, an agent of Australian encephalitis, as a model, and advanced techniques in biochemistry and electron microscopy, we have previously identified these membranes as the site of synthe ....Flaviviruses are the agents of many mosquito-transmitted infections such as encephalitis and dengue, and hepatitis C virus is a member of the same virus family. During virus multiplication in cells, new membrane structures are induced and these represent regions where the replication events occur. Using Kunjin virus, an agent of Australian encephalitis, as a model, and advanced techniques in biochemistry and electron microscopy, we have previously identified these membranes as the site of synthesis of the viral RNA or genetic material, and the viral proteins involved. These comprise the viral replication complex. The research will define the origin of these membranes, and how the components of the associated replication complex are assembled. Assembly of the virus particles in cells is also being analysed using similar technology. Hepatitis C virus cannot be reliably grown at present for research purposes in cultured cells, and we will attempt to develop a helper system to overcome the problem. An understanding of these processes, and how the viral RNA is copied into progeny RNA for new virus particles, may assist in the development of antiviral drugs for treatment of slow or persistent virus infections such as hepatitis C.Read moreRead less