Functional characterisation of the human virome through expression screens in human cells (360G-Wellcome-201387_Z_16_Z)

Viruses manipulate the machinery of their host cell to permit their efficient replication whilst simultaneously evading detection by the host immune system. Deciphering the mechanisms by which viral genes achieve these goals, therefore, is informative not only for understanding the mechanisms of viral pathogenesis, but also for elucidating the basic biology of the cell. However, no large-scale approach is currently available to identify viral genes that modulate a particular cellular pathway. I will overcome this limitation by creating a large-scale plasmid library of viral genes, which will be introduced into human cells to carry out expression screens. My primary goal is to use this approach to identify novel viral genes that antagonise the sensing of viral nucleic acids, using fluorescence-activating cell sorting (FACS) to isolate cells that - as a result of expressing a single viral gene - can no longer mount an interferon response to transfected DNA or RNA. Overall this work will 1) reveal new insights into the mechanisms by which cells respond to viral nucleic acids, and 2) develop a method that will be broadly applicable to enable the identification of viral genes that modulate theoretically any cellular process important for viral replication or immune evasion.