Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Arizona State University, Tempe, USA.
ASU-Banner Center for Neurodegenerative Diseases, Arizona State University, Tempe, USA.
Adv Exp Med Biol. 2024;1451:125-137. doi: 10.1007/978-3-031-57165-7_8.
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.
痘病毒以获得/进化了许多基因来对抗宿主固有免疫而臭名昭著。正痘病毒至少获得/进化了三种不同的宿主细胞坏死性死亡抑制剂：E3，它阻止 ZBP1 依赖性坏死性细胞死亡，以及 vIRD 和 vMLKL，它们抑制初始细胞死亡信号下游的坏死性死亡。虽然这表明坏死性细胞死亡途径在抑制正痘病毒复制中的重要性，但几种正痘病毒已经失去了一种或多种抑制功能。猴痘/猴痘病毒（MPXV）失去了其 E3 同源物的 N 端的一部分。痘苗病毒 E3 同源物的 N 端用于抑制干扰素诱导的抗病毒蛋白 ZBP1 的激活。这使得 MPXV 在正痘病毒中是独一无二的，因为它在包括人类在内的许多哺乳动物中对干扰素（IFN）治疗敏感，而人类则编码完整的坏死性细胞死亡途径。因此，IFN 敏感性可能是像 MPXV 这样的病毒的阿喀琉斯之踵，这些病毒无法完全抑制 IFN 诱导的、依赖 ZBP1 的抗病毒途径。
