Myxoma virus lacking the host range determinant M062 stimulates cGAS-dependent type 1 interferon response and unique...

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Poxviruses employ diverse strategies to evade host immune responses, particularly type 1 interferon (IFN-I) production.
• Inhibition of DNA sensing pathways is crucial for poxvirus survival, especially early in infection.
• The myxoma virus (MYXV) M062R gene is a key host range determinant essential for infection across mammalian species.

Purpose of the Study:

• To identify poxvirus gene products that suppress antiviral and proinflammatory responses.
• To investigate the function of the MYXV M062R gene, a conserved host range factor.
• To elucidate the role of M062R in inhibiting host Sterile α Motif Domain-containing 9 (SAMD9) and its impact on innate immunity.

Main Methods:

• Investigated the immunostimulatory properties of replication-defective MYXV lacking M062R (ΔM062R).
• Assessed activation of host DNA sensing pathways, including cGAS-dependent signaling.
• Utilized SAMD9 knockdown and transcriptomic analyses to evaluate host gene expression changes.

Main Results:

• Replication-defective ΔM062R MYXV activates host DNA sensing pathways in a cGAS-dependent manner.
• Knocking down SAMD9 expression significantly attenuates the proinflammatory responses induced by ΔM062R infection.
• Transcriptomic analysis revealed a distinct host gene expression profile compared to dsDNA-stimulated inflammation.

Conclusions:

• The MYXV M062R protein inhibits host DNA sensing and innate immune responses by targeting SAMD9.
• Loss of M062R function leads to potent, cGAS-dependent immune activation.
• This study links the anti-neoplastic function of SAMD9 to the regulation of poxvirus-induced innate immune responses.