Modulation of infection and defense by MERS-coronavirus protein 4b (Drosten / Hönzke)
Within the MERS-coronavirus genome, gene 4b encodes a 2´,5´-phosphodiesterase that prevents activation of RNAse L, an important interferon-stimulated antiviral effector and enhancer of the interferon response. Although the main site of activity should be the cytosol, the 4b gene encodes a nuclear localization signal that is functional, yet is lost in some virus variants. There is only minimal knowledge on phenotypic variability among MERS-coronavirus variants.
Based on viral reverse genetics and using an advanced human lung explant culture model, we will study whether loss of nuclear localization may constitute an evolutionary toggle that can lead to a sudden increase of viral replication during cross-host transmission and adaptation to humans.