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
Molecular Pathogenesis Of Emerging West Nile Viruses
Funder
National Health and Medical Research Council
Funding Amount
$594,133.00
Summary
West Nile virus (WNV) is a mosquito-borne virus that causes potentially fatal encephalitis in humans and horses. This project will investigate the recent emergence of pathogenic for horses WNV in Australia and the potential of this new isolate to cause severe disease in humans. We will define the viral and host factors determining the outcome of WNV infection. This project will provide knowledge on the factors involved in the emergence of virulent WNV strains from attenuated isolates.
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
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.
The occcurence of herpes simplex virus (HSV) in the general population is very high (up to 60%). In Central Africa, co-infection of HSV and HIV may increase HIV transmission in more than 40% of cases. HSV enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transpo ....The occcurence of herpes simplex virus (HSV) in the general population is very high (up to 60%). In Central Africa, co-infection of HSV and HIV may increase HIV transmission in more than 40% of cases. HSV enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transported back down the nerve cell processes to the skin where it causes blisters-ulcers or is shed without causing symptoms. The aim of this project is to determine how HSV is assembled within cells at the molecular level. This will lead to identification of crucial molecular interactions required for viral assembly. Such information on viral assembly will allow development of inhibitors of this process which may be candidates for use as antivirals for control of recurrent herpes simplex. These antiviral agents will be able to target key viral molecular interactions in essentially all types of cells in the body and act against other herpesviruses in general.Read moreRead less
Discovery Of A Novel Immune Evasion Strategy Employed By Mosquito Borne Viruses To Suppress Antiviral Immune Responses
Funder
National Health and Medical Research Council
Funding Amount
$418,642.00
Summary
The transition from mosquitoes, ticks, or other invertebrate vectors to the human hosts represents a crucial step in the successful establishment of arthropod borne viruses (arboviruses). The incidence of arbovirus infections such as dengue virus, West Nile virus, Ross River virus is increasing at an alarming rate in various parts of the world. In addition, the emergence of new viruses resulting in significant mortality in the population is of utmost concern. Vaccines for many of these viruses r ....The transition from mosquitoes, ticks, or other invertebrate vectors to the human hosts represents a crucial step in the successful establishment of arthropod borne viruses (arboviruses). The incidence of arbovirus infections such as dengue virus, West Nile virus, Ross River virus is increasing at an alarming rate in various parts of the world. In addition, the emergence of new viruses resulting in significant mortality in the population is of utmost concern. Vaccines for many of these viruses remain elusive. One factor that contributes to this is the ability of viruses to develop ingenious strategies to avoid or suppress the host defence systems, which enable its successful establishment in the host. Understanding how viruses evade-suppress host defence machinery will certainly enhance and improve our approaches to fight them. For the first time internationally we have discovered a new and novel pathway employed by arboviruses to suppress antiviral immune responses in the host. We have discovered that naturally occurring carbohydrates on viruses derived from mosquito cells, would influence these virus s ability to evade-suppress host antiviral proteins such as interferons. This may be a general effect of arboviruses or may even extend to other viruses , which include a number of deadly pathogens (HIV, Influenza). This research has the potential to significantly expand our understanding of how these viruses establish infection and cause disease. Also this discovery has broader implications for understanding inflammatory processes and their regulation.Read moreRead less
Functional Roles Of The Tegument Proteins Of Herpes Simplex Virus Type 1
Funder
National Health and Medical Research Council
Funding Amount
$461,597.00
Summary
The occurrence of herpes simplex virus (HSV) in the general population is very high (up to 60%). HSV enters the human body via the skin before entering nerve cells where it lies dormant in most people. Intermittently the virus reactivates and usually forms blisters at the skin when it sheds. The aim of this project is to define a molecular interaction network at the protein level during the course of infection of a host cell. This information will provide new targets for design of antivirals.
Transport And Egress Of Herpes Simplex Virus In Neurones
Funder
National Health and Medical Research Council
Funding Amount
$592,023.00
Summary
Herpes simplex virus (HSV) enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transported back down the nerve cell processes to the skin where it causes blisters-ulcers or is shed without causing symptoms. The aim of this grant is to determine how HSV is transpor ....Herpes simplex virus (HSV) enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transported back down the nerve cell processes to the skin where it causes blisters-ulcers or is shed without causing symptoms. The aim of this grant is to determine how HSV is transported within nerve cells at the molecular level. Recent discoveries have shown how virus transport in nerve cells is dependent on interactions between specific viral proteins and cellular motor proteins and how the virus escapes from nerves to infect skin and cause disease. Such information on viral transport will allow development of inhibitors of this process which may be candidates for use as antivirals for control of recurrent herpes simplex. In addition, this information will allow the virus to be exploited for use in gene therapy to introduce DNA into human nerve cells to correct genetic abnormalities. Finally this data will assist in understanding similar mechanisms for other viruses transported in nerve cells such as those causing shingles and rabies.Read moreRead less
Elucidation Of Immune Mechanisms Underlying HSV Vaccine Development
Funder
National Health and Medical Research Council
Funding Amount
$573,993.00
Summary
HSV-1 and -2 causes genital herpes, cold sores, encephalitis, potential fatal neonatal herpes, keratitis and blindness as well as severe disease in transplant patients. HSV infection also enhances the acquisition of HIV by 2-3 fold. Investigating the mechanism of immune response to HSV infection or components of HSV will assist in understanding immune control of HSV, HSV vaccine development, and assist in reducing in HIV spread.