Human cytomegalovirus controls a new autophagy-dependent cellular antiviral defense mechanism
Human cytomegalovirus controls a new autophagy-dependent cellular antiviral defense mechanism
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DOI：
10.4161/auto.5184
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发表时间：
2008-01-01
期刊：
影响因子：
13.3
通讯作者：
Esclatine, Audrey
中科院分区：
文献类型：
--
作者：
Chaumorcel, Magali;Souquere, Sylvie;Esclatine, Audrey
人巨细胞病毒（HCMV）是一种普遍存在的疱疹病毒，仍然是出生缺陷的主要感染原因，以及作为一个重要的机会致病菌。大自噬（Macroautophagy）（以下称为自噬）是一种进化上保守的过程，其负责细胞质大分子的降解，以及通过溶酶体途径消除受损的细胞器。在生物体中，压力条件和某些疾病也会触发这一过程。以前的观察表明，自噬（在这种情况下也称为异噬）可能有助于对病毒感染的先天免疫。最近对另一种疱疹病毒HSV-1的研究表明，HSV-1能够通过一种病毒蛋白ICP34.5来避免这种细胞防御，该蛋白拮抗宿主的自噬反应。然而，尚不清楚HCMV是否也能够抵消自噬。在这里，我们表明，HCMV感染大大抑制自噬体形成的原代人成纤维细胞。通过GFP-LC 3再分布、LC 3-II和p62积累和电子显微镜评估自噬。自噬的抑制在感染早期通过涉及病毒蛋白的机制发生。事实上，只有表达病毒蛋白的感染细胞显示出自噬的显著减少;而旁观者，未感染的细胞显示出与对照细胞相似的自噬水平。HCMV激活mTOR信号通路，并使感染的细胞对雷帕霉素诱导的自噬产生抗性。此外，受感染的细胞也对氯化锂（一种mTOR非依赖性自噬诱导剂）刺激自噬产生抗性。这些发现表明，HCMV已开发出有效的策略，在感染过程中阻断自噬的诱导。
Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that remains the major infectious cause of birth defects, as well as being an important opportunistic pathogen. Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved process responsible for the degradation of cytoplasmic macromolecules, and the elimination of damaged organelles via a lysosomal pathway. This process is also triggered in organisms by stressful conditions and by certain diseases. Previous observations have suggested that autophagy (also known as xenophagy in this case) may contribute to innate immunity against viral infections. Recent studies on HSV-1, another herpesvirus, have shown that HSV-1 is able to avoid this cellular defense by means of a viral protein, ICP34.5, which antagonizes the host autophagy response. However, it was not known whether HCMV was also able to counteract autophagy. Here, we show that HCMV infection drastically inhibits autophagosome formation in primary human fibroblasts. Autophagy was assessed by GFP-LC3 redistribution, LC3-II and p62 accumulation and electron microscopy. Inhibition of autophagy occurred early in the infection by a mechanism involving viral protein(s). Indeed, only infected cells expressing viral proteins displayed a striking decrease of autophagy; whereas bystander, non-infected cells displayed a level of autophagy similar to that of control cells. HCMV activated the mTOR signaling pathway, and rendered infected cells resistant to rapamycin-induced autophagy. Moreover, infected cells also became resistant to the stimulation of autophagy by lithium chloride, an mTOR-independent inducer of autophagy. These findings suggest that HCMV has developed efficient strategies for blocking the induction of autophagy during infection.