25-Hydroxycholesterol and 27-hydroxycholesterol inhibit human rotavirus infection by sequestering viral particles into late endosomes.
25-Hydroxycholesterol and 27-hydroxycholesterol inhibit human rotavirus infection by sequestering viral particles into late endosomes.
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DOI：
10.1016/j.redox.2018.09.003
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发表时间：
2018-10
期刊：
影响因子：
11.4
通讯作者：
Lembo D
中科院分区：
文献类型：
--
作者：
Civra A;Francese R;Gamba P;Testa G;Cagno V;Poli G;Lembo D
一种新的先天免疫策略，包括特定的胆固醇氧化产物作为效应器，已经开始揭示胆固醇代谢与对抗病毒感染的免疫反应之间的联系。事实上，25-羟基胆固醇（25HC）和27-羟基胆固醇（27HC）是由胆固醇酶氧化生理产生的，可作为广泛的包膜和非包膜人类病毒的抑制剂。然而，它们对非包膜病毒的保护作用的机制几乎完全未被探索。为了深入了解这一领域，我们研究了25HC和27HC对一种引起儿童急性胃肠炎的非包膜病毒——人轮状病毒（HRV）的抗病毒活性。我们发现25HC和27HC在低微摩尔范围内以50%的抑制浓度阻断几种HRV菌株的传染性，而没有细胞毒性。这两种分子通过阻止两种细胞蛋白的结合来影响病毒侵入细胞的最后一步：氧甾醇结合蛋白（OSBP）和囊泡相关膜蛋白相关蛋白-a （VAP-A）。通过改变这些细胞介质的活性，25HC和27HC干扰内质网和后期核内体之间胆固醇的再循环，而后者被HRV利用进入细胞。后期内体腔室中胆固醇的大量积累导致病毒颗粒被隔离在这些囊泡内，从而阻止细胞质病毒复制。这些发现表明，酶源性胆固醇氧化产物可能是宿主限制策略对抗HRV感染的主要效应物，并指出氧化还原活性脂质参与病毒感染是一个重点研究领域，以便更好地关注，以确定新的抗病毒药物靶点。
A novel innate immune strategy, involving specific cholesterol oxidation products as effectors, has begun to reveal connections between cholesterol metabolism and immune response against viral infections. Indeed, 25-hydroxycholesterol (25HC) and 27-hydroxycholesterol (27HC), physiologically produced by enzymatic oxidation of cholesterol, act as inhibitors of a wide spectrum of enveloped and non-enveloped human viruses. However, the mechanisms underlying their protective effects against non-enveloped viruses are almost completely unexplored. To get insight into this field, we investigated the antiviral activity of 25HC and 27HC against a non-enveloped virus causing acute gastroenteritis in children, the human rotavirus (HRV). We found that 25HC and 27HC block the infectivity of several HRV strains at 50% inhibitory concentrations in the low micromolar range in the absence of cell toxicity. Both molecules affect the final step of virus penetration into cells by preventing the association of two cellular proteins: the oxysterol binding protein (OSBP) and the vesicle-associated membrane protein-associated protein-A (VAP-A). By altering the activity of these cellular mediators, 25HC and 27HC disturb the recycling of cholesterol between the endoplasmic reticulum and the late endosomes which are exploited by HRV to penetrate into the cell. The substantial accumulation of cholesterol in the late endosomal compartment results in sequestering viral particles inside these vesicles thereby preventing cytoplasmic virus replication. These findings suggest that cholesterol oxidation products of enzymatic origin might be primary effectors of host restriction strategies to counteract HRV infection and point to redox active lipids involvement in viral infections as a research area of focus to better focus in order to identify novel antiviral agents targets.
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影响因子：
32.4
作者：
Blanc M;Hsieh WY;Robertson KA;Kropp KA;Forster T;Shui G;Lacaze P;Watterson S;Griffiths SJ;Spann NJ;Meljon A;Talbot S;Krishnan K;Covey DF;Wenk MR;Craigon M;Ruzsics Z;Haas J;Angulo A;Griffiths WJ;Glass CK;Wang Y;Ghazal P
通讯作者：
Ghazal P
DOI：
10.1073/pnas.1404271111
发表时间：
2014-07-22
影响因子：
11.1
作者：
Gold, Elizabeth S.;Diercks, Alan H.;Aderem, Alan
通讯作者：
Aderem, Alan
影响因子：
4.8
作者：
Infante, Rodney E.;Abi-Mosleh, Lina;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.
影响因子：
30.3
作者：
Amini-Bavil-Olyaee S;Choi YJ;Lee JH;Shi M;Huang IC;Farzan M;Jung JU
通讯作者：
Jung JU
影响因子：
168.9
作者：
Kotloff, Karen L.;Nataro, James P.;Levine, Myron M.
通讯作者：
Levine, Myron M.