The varicella-zoster virus ORF47 kinase interferes with host innate immune response by inhibiting the activation of IRF3.

The innate immune response constitutes the first line of host defence that limits
viral spread and plays an important role in the activation of adaptive immune
response. Viral components are recognized by specific host pathogen recognition
receptors triggering the activation of IRF3. IRF3, along with NF-kappaB, is a key
regulator of IFN-beta expression. Until now, the role of IRF3 in the activation
of the innate immune response during Varicella-Zoster Virus (VZV) infection has
been poorly studied. In this work, we demonstrated for the first time that VZV
rapidly induces an atypical phosphorylation of IRF3 that is inhibitory since it
prevents subsequent IRF3 homodimerization and induction of target genes. Using a
mutant virus unable to express the viral kinase ORF47p, we demonstrated that (i)
IRF3 slower-migrating form disappears; (ii) IRF3 is phosphorylated on serine 396
again and recovers the ability to form homodimers; (iii) amounts of IRF3 target
genes such as IFN-beta and ISG15 mRNA are greater than in cells infected with the
wild-type virus; and (iv) IRF3 physically interacts with ORF47p. These data led
us to hypothesize that the viral kinase ORF47p is involved in the atypical
phosphorylation of IRF3 during VZV infection, which prevents its homodimerization
and subsequent induction of target genes such as IFN-beta and ISG15.