The IκB Kinases Restrict Human Cytomegalovirus Infection.
The IκB Kinases Restrict Human Cytomegalovirus Infection.
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IκB 激酶限制人类巨细胞病毒感染。
DOI：
10.1128/jvi.02030-18
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发表时间：
2019
影响因子：
5.4
通讯作者：
Munger,Joshua
中科院分区：
文献类型：
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作者：
Goodwin,ChristopherM;Munger,Joshua
人类巨细胞病毒 (HCMV) 是一种普遍存在的疱疹病毒，可在免疫抑制人群中引起疾病。 HCMV 与先天免疫信号通路有着复杂的关系。具体来说，HCMV 被发现可以阻断炎症信号传导的某些方面，同时受益于其他方面。通过对针对 NF-κB 调节激酶 IκB 激酶 α (IKKα) 和 IKKβ 的敲除细胞系的分析，我们发现 IKK 是宿主限制因子，有助于细胞因子介导的病毒感染抵抗、限制 HCMV 感染的启动并减弱病毒细胞间传播。 HCMV UL26 蛋白是一种对 HCMV 感染很重要的病毒免疫调节剂，已被证明可以抑制宿主细胞 NF-κB 信号传导，但目前尚不清楚 UL26 介导的 NF-κB 调节如何促进感染。在这里，我们发现 UL26 对 NF-κB 信号传导的调节与其对高滴度病毒复制的贡献是分开的。然而，我们发现 IKKβ 是诱导与 ΔUL26 感染相关的细胞因子表达所必需的。总的来说，我们的数据表明 IKK 限制感染，但 HCMV 以它们的信号传导为目标来调节细胞炎症环境。重要性先天免疫信号传导是针对病毒感染的关键防御，代表了经常决定感染结果的核心宿主-病毒相互作用。 NF-κB 信号传导是先天免疫的重要组成部分，受到 HCMV 的广泛调节，是新生儿和免疫抑制个体发病的重要原因。然而，NF-κB 信号传导的各个方面在 HCMV 感染期间发挥的作用仍然难以捉摸。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，在缺乏病毒编码的 NF-κB 抑制剂 UL26 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实现以该通路为治疗目标的可能性的重要第一步。
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 UL26 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 UL26-mediated NF-κB modulation contributes to infection. Here, we find that UL26 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 ΔUL26 infection. Collectively, our data indicate that the IKKs restrict infection but HCMV targets their signaling to modulate the cellular inflammatory environment.IMPORTANCEInnate 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, UL26. 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.