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.
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.
Viral And Host Factors Determining Outcome Of Zika Virus Infection
Funder
National Health and Medical Research Council
Funding Amount
$910,780.00
Summary
The proposal aims at identifying viral and host factors determining outcomes of infection with Zika virus, a significant mosquito-transmitted pathogen associated with debilitating neurological pathology in new-borne babies from mothers infected during pregnancy. We will use cutting edge methodologies and infections models to bring our understanding of Zika virus infection to unprecedented level. The results could also facilitate identification of targets for effective anti-viral therapy.
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
Inhibitors Of West Nile Virus Protease As Antiviral Drugs
Funder
National Health and Medical Research Council
Funding Amount
$590,740.00
Summary
The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in people i ....The West Nile Virus (WNV) was first isolated from a woman in the West Nile region of Uganda in 1937. It is one of ~70 known flaviviruses (e.g. Dengue fever, Yellow fever, West Nile, Kunjun, Japanese encephalitis, St. Louis encephalitis, tick-borne encephalitis, Australian encephalitis and the related hepatitis C virus) which annually infect hundreds of millions of people worldwide, particularly in tropical and sub-tropical areas, and cause major public health problems. WNV is endemic in people in the Middle East, parts of Africa and Europe, but recent epidemics in Israel (1998), Romania (1996), United States (1999), and UK (2003), that have been traced to migratory birds, were characterized by severe symptoms , severe neurological pathology, and fatalities. In the USA alone there were 4,156 infections and 284 deaths in 2002, 9122 infections and 223 deaths in 2003, and this mosquito borne virus has quickly spread since 1999 through all USA states and into Canada and Mexico (http:--www.cdc.gov-ncidod-dvbid- westnile-index.htm). No treatments or vaccines are available. This project focuses on a viral enzyme, known as the West Nile Virus NS3 protease, that is essential for replication of the virus. By studying the enzyme in the laboratory we can design small molecules that block its function and these are potential leads for developing drug treatments for people infected, not only by this virus but potentially also other flaviviruses. A precedent is the success of inhibitors of HIV-1 protease that are the most effective treatment for humans with HIV-infections, and other viral proteases are now becoming recognized as viable antiviral targets for pharmaceutical development. The project involves experts on small molecule protease inhibitor design and development, proteases, and virology including West Nile virology. We expect to generate new information at the cutting edge of West Nile Virus and flavivirus research and promising new antiviral drug candidates.Read moreRead less
The Role Of Noncoding Subgenomic Flavivirus RNA In Virus-host Interactions
Funder
National Health and Medical Research Council
Funding Amount
$624,429.00
Summary
Flaviviruses such as Dengue, Japanese encephalitis , and West Nile are major human pathogens causing more than 50 million infections per year. Elements in viral genome responsible for pathogenesis of these viruses are not well defined. Recently we have identified a unique for these viruses noncoding subgenomic flavivirus RNA (sfRNA) and showed that it is contributing to viral pathogenesis. In this proposal we aim to determine mechanisms by which sfRNA facilitates viral pathogenesis.
Viral Factors Involved In Flavivirus Replication And Virus-host Interactions
Funder
National Health and Medical Research Council
Funding Amount
$743,696.00
Summary
With our increased understanding of virus-host interactions it has become apparent that small, non-structural proteins and small RNAs of most viruses are vital for numerous, often multiple, functions in the viral life cycle. In the proposed project, we seek to gain a detailed understanding of the functions of small nonstructural protein NS2A and small abundant viral RNAs of medicaly important encephalitic flaviviruses, which have remained so far elusive and are at the cutting-edge in the researc ....With our increased understanding of virus-host interactions it has become apparent that small, non-structural proteins and small RNAs of most viruses are vital for numerous, often multiple, functions in the viral life cycle. In the proposed project, we seek to gain a detailed understanding of the functions of small nonstructural protein NS2A and small abundant viral RNAs of medicaly important encephalitic flaviviruses, which have remained so far elusive and are at the cutting-edge in the research field. We anticipate that with a better understanding of the roles of these factors in flaviviral replication and pathogenesis, novel targets for antiviral therapies and-or molecular determinants for inclusion in candidate vaccines will be identified.Read moreRead less
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