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Type I Interferon: Monkeypox/Mpox Viruses Achilles Heel?
Jacqueline Williams1,2,3, James Bonner1,2,3,4, Karen Kibler1,2,3
1Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Arizona State University, Tempe, USA.
Abstract:
Poxviruses are notorious for having acquired/evolved numerous genes to counteract host innate immunity. Chordopoxviruses have acquired/evolved at least three different inhibitors of host necroptotic death: E3, which blocks ZBP1-dependent necroptotic cell death, and vIRD and vMLKL that inhibit necroptosis downstream of initial cell death signaling. While this suggests the importance of the necroptotic cell death pathway in inhibiting chordopoxvirus replication, several chordopoxviruses have lost one or more of these inhibitory functions. Monkeypox/mpox virus (MPXV) has lost a portion of the N-terminus of its E3 homologue. The N-terminus of the vaccinia virus E3 homologue serves to inhibit activation of the interferon-inducible antiviral protein, ZBP1. This likely makes MPXV unique among the orthopoxviruses in being sensitive to interferon (IFN) treatment in many mammals, including humans, which encode a complete necroptotic cell death pathway. Thus, IFN sensitivity may be the Achille's Heel for viruses like MPXV that cannot fully inhibit IFN-inducible, ZBP1-dependent antiviral pathways.
Insights
Monkeypox virus (MPXV) is sensitive to interferon treatment because it cannot fully block Z- Как это перевести на русский язык?BP1-dependent antiviral pathways. This inability to inhibit necroptotic cell death is a key vulnerability for MPXV.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Poxviruses possess numerous genes to evade host innate immunity.
- Chordopoxviruses encode at least three inhibitors of necroptotic cell death: E3, vIRD, and vMLKL.
- The necroptotic pathway is crucial for inhibiting chordopoxvirus replication.
Purpose of the Study:
- To investigate the implications of lost necroptotic inhibitors in chordopoxviruses.
- To understand the unique interferon sensitivity of Monkeypox virus (MPXV).
Main Methods:
- Comparative analysis of poxvirus E3 homologues.
- Examination of Z-BP1 activation and necroptosis inhibition.
- Assessment of MPXV sensitivity to interferon (IFN) treatment.
Main Results:
- MPXV has a truncated E3 homologue, lacking the N-terminal domain.
- This truncation impairs the inhibition of interferon-inducible Z-BP1.
- MPXV exhibits sensitivity to IFN treatment in mammals with complete necroptotic pathways.
Conclusions:
- The inability to fully inhibit Z-BP1-dependent antiviral pathways is a significant vulnerability for MPXV.
- Interferon sensitivity represents an Achilles' heel for poxviruses like MPXV that cannot fully suppress innate antiviral mechanisms.
- Understanding these viral evasion strategies is critical for developing effective antiviral therapies.
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