Targeting DNA-PK is a highly conserved poxvirus innate immune evasion mechanism

The sensing of viral nucleic acid by pattern recognition receptors (PRRs) is essential for initiation of a type-I interferon response against infection. Intracellular DNA sensing PRRs are responsible for initiating innate immune responses to poxviruses and other double-stranded DNA viruses. Poxviruses, in turn, encode an armoury of immunomodulators that inhibit this host defence mechanism. DNA-dependent protein kinase (DNA-PK) is an essential component of the cGAS/STING-dependent viral DNA sensing machinery that leads to the initiation of a type-I interferon response during poxvirus infection. Poxviruses counter this host sensing mechanism using the OPG020/OPG031 family of proteins that target DNA-PK, interfering with its ability to bind viral DNA. Although the DNA-PK complex, known also for its role in double strand break repair, is present across multiple taxa, its function in innate immunity outside mammals is unexplored. Here we analysed the contribution of DNA-PK to viral DNA sensing in chickens, a species that is evolutionarily distant from mammals, but that is also infected by poxviruses. We found that DNA-PK functions as a DNA sensor in chickens, and this process is countered by OPG020/OPG031 family members found in fowlpox virus. This host/pathogen interaction is conserved in a broader range of species than other mechanisms of poxvirus antagonism of innate immune sensing, which may reflect the difficulty of the host in evolving escape mechanisms that interfere with a protein that is essential for maintenance of genomic stability