Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA.
Department of Biochemistry and Biophysics, School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA
J Virol. 2019 Apr 17;93(9). doi: 10.1128/JVI.02030-18. Print 2019 May 1.
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that causes disease in immunosuppressed populations. HCMV has a complex relationship with innate immune signaling pathways. Specifically, HCMV has been found to block some aspects of inflammatory signaling while benefiting from others. Through analysis of knockout cell lines targeting the NF-κB regulatory kinases IκB kinase α (IKKα) and IKKβ, we find that the IKKs are host restriction factors that contribute to cytokine-mediated resistance to viral infection, limit the initiation of HCMV infection, and attenuate viral cell-to-cell spread. The HCMV U26 protein is a viral immune modulator important for HCMV infection that has been shown to inhibit host cell NF-κB signaling, yet it has remained unclear how U26-mediated NF-κB modulation contributes to infection. Here, we find that U26 modulation of NF-κB signaling is separable from its contribution to high-titer viral replication. However, we find that IKKβ is required for the induction of cytokine expression associated with ΔU26 infection. Collectively, our data indicate that the IKKs restrict infection but HCMV targets their signaling to modulate the cellular inflammatory environment. Innate immune signaling is a critical defense against viral infection and represents a central host-virus interaction that frequently determines the outcomes of infections. NF-κB signaling is an essential component of innate immunity that is extensively modulated by HCMV, a significant cause of morbidity in neonates and immunosuppressed individuals. However, the roles that various facets of NF-κB signaling play during HCMV infection have remained elusive. We find that the two major regulatory kinases in this pathway, IKKα and IKKβ, limit the initiation of infection, viral replication, and cell-to-cell spread. In addition, our results indicate that these kinases contribute differently to the host cell response to infection in the absence of a virally encoded NF-κB inhibitor, U26. Given the importance of NF-κB in viral infection, elucidating the contributions of various NF-κB constituents to infection is an essential first step toward the possibility of targeting this pathway therapeutically.
人类巨细胞病毒（HCMV）是一种普遍存在的疱疹病毒，会导致免疫抑制人群患病。HCMV 与先天免疫信号通路有着复杂的关系。具体来说，已经发现 HCMV 阻断了炎症信号的某些方面，同时又受益于其他方面。通过针对 NF-κB 调节激酶 IκB 激酶 α（IKKα）和 IKKβ 的敲除细胞系进行分析，我们发现 IKKs 是宿主限制因子，有助于细胞因子介导的抗病毒感染抗性，限制 HCMV 感染的起始，并减弱病毒细胞间传播。HCMV U26 蛋白是一种重要的病毒免疫调节剂，对 HCMV 感染至关重要，已被证明可抑制宿主细胞 NF-κB 信号，但 U26 介导的 NF-κB 调节如何促进感染仍不清楚。在这里，我们发现 U26 对 NF-κB 信号的调节与其对高滴度病毒复制的贡献是可分离的。然而，我们发现 IKKβ 是与 ΔU26 感染相关的细胞因子表达诱导所必需的。总之，我们的数据表明 IKKs 限制了感染，但 HCMV 针对它们的信号来调节细胞炎症环境。先天免疫信号是抵抗病毒感染的关键防御机制，是宿主与病毒相互作用的核心，经常决定感染的结果。NF-κB 信号是先天免疫的一个重要组成部分，广泛受到 HCMV 的调节，HCMV 是新生儿和免疫抑制个体发病率的重要原因。然而，NF-κB 信号在 HCMV 感染过程中的各个方面所扮演的角色仍然难以捉摸。我们发现该途径中的两个主要调节激酶，IKKα 和 IKKβ，限制了感染的起始、病毒复制和细胞间传播。此外，我们的结果表明，在没有病毒编码的 NF-κB 抑制剂 U26 的情况下，这些激酶对宿主细胞对感染的反应有不同的贡献。鉴于 NF-κB 在病毒感染中的重要性，阐明各种 NF-κB 成分对感染的贡献是通过该途径进行治疗性靶向的重要第一步。
