Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types
Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types
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DOI：
10.1128/jvi.02651-15
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发表时间：
2016-02-01
影响因子：
5.4
通讯作者：
Spector, Deborah H.
中科院分区：
文献类型：
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作者：
Belzile, Jean-Philippe;Sabalza, Maite;Spector, Deborah H.
人巨细胞病毒（HCMV）是出生缺陷的主要病毒原因，也是免疫功能低下个体的严重问题，并与动脉粥样硬化有关。先前的研究表明，自噬的诱导可以抑制几种不同类型的DNA和RNA病毒的复制。本研究的目的是确定自噬的组成性激活是否也会阻断HCMV的复制。大多数先前的研究已经使用了通过抑制mTOR途径诱导自噬的药剂。然而，由于HCMV感染改变了含mTOR激酶的复合物对抑制剂的敏感性，我们寻求了诱导自噬的替代方法。我们选择使用海藻糖，这是一种无毒的天然二糖，存在于植物、昆虫、微生物和无脊椎动物中，但不存在于哺乳动物中，并通过mTOR非依赖性机制诱导自噬。考虑到HCMV的许多不同细胞靶点，我们继续确定海藻糖是否会抑制人成纤维细胞、主动脉内皮细胞和人胚胎干细胞衍生的神经细胞中的HCMV感染。我们发现，在所有这些细胞类型中，海藻糖诱导自噬并抑制HCMV基因表达和无细胞病毒的产生。用海藻糖处理HCMV感染的神经细胞也抑制了细胞相关病毒的产生，并部分阻断了神经突生长和巨细胞的减少。这些结果表明，天然糖海藻糖或其他安全的mTOR非依赖性药物激活自噬可能为治疗HCMV疾病提供一种新的治疗方法。
Human cytomegalovirus (HCMV) is the major viral cause of birth defects and a serious problem in immunocompromised individuals and has been associated with atherosclerosis. Previous studies have shown that the induction of autophagy can inhibit the replication of several different types of DNA and RNA viruses. The goal of the work presented here was to determine whether constitutive activation of autophagy would also block replication of HCMV. Most prior studies have used agents that induce autophagy via inhibition of the mTOR pathway. However, since HCMV infection alters the sensitivity of mTOR kinase-containing complexes to inhibitors, we sought an alternative method of inducing autophagy. We chose to use trehalose, a nontoxic naturally occurring disaccharide that is found in plants, insects, microorganisms, and invertebrates but not in mammals and that induces autophagy by an mTOR-independent mechanism. Given the many different cell targets of HCMV, we proceeded to determine whether trehalose would inhibit HCMV infection in human fibroblasts, aortic artery endothelial cells, and neural cells derived from human embryonic stem cells. We found that in all of these cell types, trehalose induces autophagy and inhibits HCMV gene expression and production of cell-free virus. Treatment of HCMV-infected neural cells with trehalose also inhibited production of cell-associated virus and partially blocked the reduction in neurite growth and cytomegaly. These results suggest that activation of autophagy by the natural sugar trehalose or other safe mTOR-independent agents might provide a novel therapeutic approach for treating HCMV disease.