The role of translational control in the natural history of measles virus
Lead Research Organisation:
Queen's University Belfast
Department Name: Sch of Biomedical Sciences
Abstract
Fever in humans is generally unwelcome and we try to alleviate it by taking drugs and shedding clothes. Our study centres on measles virus (MV) which induces a high fever. Viruses evolve alongside their hosts; so whenever the host tweaks its immune system to fight the virus the virus responds by collecting additional genes or mutating existing ones to circumvent this assault. Understanding this race is vitally important. MV has two proteins which are essential for growth and when the virus replicates at 37°C the proteins are produced. However, when MV grows at 39°C, a similar temperature experienced during fever, these proteins are not made. This potentially gives the virus an advantage during fever, since when these proteins are not made the virus can hide within cells and evade detection by the immune system. The work will be led by Bert Rima, who has worked for over 30 years on MV, and Paul Duprex who has genetically modified viruses to study links between their genes and proteins. We are in an ideal position to address this problem because we can both manipulate the virus and have established animal models which allow us to differentiate between disease-causing and non-disease-causing viruses.
Technical Summary
Fever is a hallmark response to infection. From a physiological perspective, the rise in body temperature is a process which aims to ensure survival of the individual. Endogenous pyrogens such as the cytokines interleukins 1, 6 and tumour necrosis factor act in concert on thermoregulatory centres in the hypothalamus to generate a controlled elevation in temperature.
Co-evolution of host and pathogen is common. As fever is deemed to be an evolutionary adaptation to infection, one may hypothesise that unidentified mechanisms have evolved to capitalise on the innate febrile response to virus infection, similar to the variety of mechanisms that viruses use to abrogate immune responses. Interestingly, this idea has not been studied in any detail and as such both virologists and clinicians have no real understanding of how infectious agents might exploit this response.
Measles virus (MV) provides us with a unique opportunity to study this effect for a number of reasons. First, fever is clinically typical of MV infection; second, we have published that two important structural proteins of the virus are selectively translated at elevated temperatures; third we can manipulate the viral genome by reverse genetics and thereby generate recombinant viruses with altered phenotypes and last we have established a number of animal models which allow us complement in vitro mechanistic studies on selective temperature-sensitive translation with an in vivo pathological assessment.
We propose a four year programme of work which aims to understand the molecular basis for selective temperature-sensitive expression translation (StsT) of the matrix (M) and fusion (F) proteins of MV. This effect has been identified in vaccine viruses and a single wild-type virus. We will determine if it is demonstrable in other wild-type viruses and a closely related animal virus, canine distemper virus. Eukaryotic expression constructs expressing the individual genes will be used to examine StsT in transfected cells and determine if the effect is wholly or partially dependent on the expression of other viral proteins or the generation of an infected state within cells. These approaches will allow us to map the viral sequences which govern StsT and permit us to generate recombinant viruses which have the sequences removed. These viruses will be phenotypically characterised using appropriate animal models to elucidate the in vivo consequences. At a molecular level proteins which recognise the StsT sequences will be identified using proteomic-based approaches.
Co-evolution of host and pathogen is common. As fever is deemed to be an evolutionary adaptation to infection, one may hypothesise that unidentified mechanisms have evolved to capitalise on the innate febrile response to virus infection, similar to the variety of mechanisms that viruses use to abrogate immune responses. Interestingly, this idea has not been studied in any detail and as such both virologists and clinicians have no real understanding of how infectious agents might exploit this response.
Measles virus (MV) provides us with a unique opportunity to study this effect for a number of reasons. First, fever is clinically typical of MV infection; second, we have published that two important structural proteins of the virus are selectively translated at elevated temperatures; third we can manipulate the viral genome by reverse genetics and thereby generate recombinant viruses with altered phenotypes and last we have established a number of animal models which allow us complement in vitro mechanistic studies on selective temperature-sensitive translation with an in vivo pathological assessment.
We propose a four year programme of work which aims to understand the molecular basis for selective temperature-sensitive expression translation (StsT) of the matrix (M) and fusion (F) proteins of MV. This effect has been identified in vaccine viruses and a single wild-type virus. We will determine if it is demonstrable in other wild-type viruses and a closely related animal virus, canine distemper virus. Eukaryotic expression constructs expressing the individual genes will be used to examine StsT in transfected cells and determine if the effect is wholly or partially dependent on the expression of other viral proteins or the generation of an infected state within cells. These approaches will allow us to map the viral sequences which govern StsT and permit us to generate recombinant viruses which have the sequences removed. These viruses will be phenotypically characterised using appropriate animal models to elucidate the in vivo consequences. At a molecular level proteins which recognise the StsT sequences will be identified using proteomic-based approaches.