Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types

被引:65
作者
Belzile, Jean-Philippe
Sabalza, Maite
Craig, Megan
Clark, Alex E.
Morello, Christopher S.
Spector, Deborah H. [1 ]
机构
[1] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA
基金
美国国家卫生研究院;
关键词
AMYOTROPHIC-LATERAL-SCLEROSIS; ENDOTHELIAL-CELLS; CYTOPLASMIC COMPARTMENT; MOUSE MODEL; STEM-CELLS; VIRUS; FLUX; MACHINERY; PATHOLOGY; GENES;
D O I
10.1128/JVI.02651-15
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页码:1259 / 1277
页数:19
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