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
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
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
Wolbachia And West Nile Virus In Mosquitoes: Friends Or Foes?
Funder
National Health and Medical Research Council
Funding Amount
$561,028.00
Summary
Mosquito-borne viruses pose a great risk to human and animal health. Presence of compentent vectors of several viruses in Australia indicates vulnerability of Australia’s biosecurity. This project will define the mechanisms of inhibition of virus replication in mosquitoes by a symbiotic bacterium which can be utilized in virus inhibition.
Role Of Flavivirus-encoded Small Regulatory RNAs In Virus-mosquito Vector Interactions
Funder
National Health and Medical Research Council
Funding Amount
$547,216.00
Summary
Mosquito-borne diseases are major threats to human health. MicroRNAs are small non-coding ribonucleic acids (RNAs) that play important roles in development, cancer, apoptosis, immunity, longevity, and viral infections. We propose to identify the regulatory microRNAs from flaviviruses and establish their potential function in vector-arboviruses interactions. The project will put Australia at the forefront of research in the most rapidly developing area of microRNA research.
Cellular Microenvironments Facilitating The Replication And Propagation Of Flaviviruses
Funder
National Health and Medical Research Council
Funding Amount
$505,279.00
Summary
Flaviviruses are the agents of many mosquito-transmitted infections and many deaths globally each year. The emerging virus West Nile virus (strain New York) is a member of this virus family and shares 99% amino acid homology with the endemic Australian virus Kunjin virus. During virus growth in cells, cellular membrane structures are induced or rearranged by these viruses for their own purpose. That being the production of more virus particles for reinfection of other cells. Using Kunjin virus a ....Flaviviruses are the agents of many mosquito-transmitted infections and many deaths globally each year. The emerging virus West Nile virus (strain New York) is a member of this virus family and shares 99% amino acid homology with the endemic Australian virus Kunjin virus. During virus growth in cells, cellular membrane structures are induced or rearranged by these viruses for their own purpose. That being the production of more virus particles for reinfection of other cells. Using Kunjin virus as a model, and advanced techniques in biochemistry and electron microscopy, we have identified for the first time these membrane structures as the apparent sites of replication of the viral RNA or genetic material, and of the viral proteins involved. We have also observed how new virus particles are able to get out of infected cells and shown how some drugs can prevent this occurring thus limiting their transmission. This research will focus on how the membrane structures are formed in infected cells. The research will determine what cellular components are required by the virus to help it propagate. In particular specific cellular proteins and membrane components that are captured by the virus and moved to different sites in the infected cells. These apparent requirements could possibly lead us to a greater understanding of the complex interactions that occur between the invading virus and the host cells. We aim to directly visualize the process of infection within living cells using new and innovative microscopic techniques. Another of our objectives is to determine the effects of infection on normal cells. The question being whether flavivirus infection disrupts normalcell fuctions like secretion etc. An understanding of these processes, and how the viral RNA is copied into new RNA for more virus particles, will assist in the development of antiviral drugs for treatment of this pathogenic group of viruses.Read moreRead less
Chimeric Insect-specific Flaviviruses: A New Generation Of Diagnostics And Vaccines Against Mosquito-borne Viral Disease
Funder
National Health and Medical Research Council
Funding Amount
$549,937.00
Summary
Dengue, Zika and West Nile are mosquito-borne viruses that cause disease outbreaks world-wide. We will develop safe, cheap and authentic diagnostics and vaccines against these diseases based on novel viruses that only infect mosquitoes. This is a timely paradigm shift for vaccine and diagnostic development. This innovative strategy will have high impact in the field of vector-borne viral diseases and provide a blueprint to develop safe diagnostics and vaccines for other mosquito-borne diseases.
Needle Free Delivery Of Dengue And Zika Vaccines To The Skin
Funder
National Health and Medical Research Council
Funding Amount
$642,792.00
Summary
There is no Zika vaccine and only one licensed dengue vaccine, which is age and region restricted because of poor efficacy. We have developed safe subunit vaccine candidates capable of inducing potent virus neutralizing antibodies and demonstrated protection from lethal dengue challenge in a mouse model. Here we are partnering with Vaxxas to undertake preclinical development and GLP toxicity trials for microarray patches delivering dengue and zika virus subunit vaccines.
The Role Of Noncoding Viral RNAs In Flavivirus Infection And Exosomal Signalling
Funder
National Health and Medical Research Council
Funding Amount
$683,447.00
Summary
The application is aimed at investigating the novel role for viral noncoding RNAs in exosomal antiviral signalling and associated outcome of infection with West Nile virus. We will identify host enzymes involved in generation of viral noncoding RNAs, determine which host proteins they interact with and how these interactions determine their incorporation into secreted exosomes to influence outcome of infection.