Antagonizing the SAMD9 pathway is key to myxoma virus host shut-off and immune evasion

Poxviruses have life cycles exclusively in the cytoplasm. However, these viruses can have profound impact to host transcription. One possible mechanism is through viral manipulation of host protein synthesis and such ability is critical for viral immune evasion. Many mammalian poxviruses encode more than one viral protein to interact with the host SAMD9 protein. In myxoma virus (MYXV), a rabbit specific poxvirus and non-pathogenic for other species, viral M062 protein is the lone inhibitor to SAMD9 with broad species specificity and loss of M062R in viral genome (Δ M062R mutant) leads to profound infection defect. We previously found Δ M062R remodeled transcriptomic landscape in monocytes/macrophages that is associated with the crosstalk between the SAMD9 pathway and cGAS/STING/IRF3 DNA sensing pathway. In this study we completed the characterization of Δ M062R infection. We observed that although this replication-defective virus preserved intact early protein synthesis, it failed to conduct host shutoff. Despite a defect in viral DNA replication, Δ M062R infection retained intact intermediate protein synthesis comparable to the wildtype virus. Using time course dual RNAseq analyses we found that the overall viral gene transcription profile was mostly indistinguishable from that of the wildtype MYXV. However, the slightly attenuated late RNA synthesis along with the block at viral protein synthesis led to its infection defect. Infection by Δ M062R in macrophages potentiated the antiviral responses to new danger signals. We provided an initial characterization of such a state in which host antiviral protein synthesis may be promoted leading to the immunological consequence.