Abstract
AbstractPoxviruses 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 ofM062Rin viral genome (ΔM062Rmutant) leads to profound infection defect. We previously found ΔM062Rremodeled 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 ΔM062Rinfection. 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, ΔM062Rinfection 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 ΔM062Rin 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.ImportancePoxviruses utilize multi-faceted strategies to evade and manipulate host immunity. Through targeted gene deletion, we generated useful tools of mutant poxviruses to investigate specific crosstalk between host defense mechanisms. Through studying MYXV M062 protein function, we previously identified SAMD9 as one host target of poxvirusC7Lsuperfamily, in which familyM062Ris one member. However, what kind of cellular outcome caused by ΔM062Rinfection remained unknown. The infection defect of ΔM062Rcaused the induction of host inflammation program is likely due to the activation of the host pathway governed by SAMD9. Because little is known about SAMD9 cellular function and the pathways it regulates, which are important for cellular homeostasis and immune regulation, this study on ΔM062Rinduced effect in host cells will provide new insight on how SAMD9 affects cellular protein synthesis and immunological responses.
Publisher
Cold Spring Harbor Laboratory