Cyclosporin a inhibits rotavirus replication and restores interferon-beta signaling pathway in vitro and in vivo.
Cyclosporin a inhibits rotavirus replication and restores interferon-beta signaling pathway in vitro and in vivo.
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环孢菌素 A 在体外和体内抑制轮状病毒复制并恢复干扰素-β 信号通路
DOI：
10.1371/journal.pone.0071815
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Shen Z;He H;Wu Y;Li J
轮状病毒(RV)是婴幼儿严重腹泻的最常见原因。目前，还没有针对轮状病毒的特效药，这主要是因为缺乏理想的靶分子，这阻碍了药物的开发。我们以前的研究表明，环孢素A(CsA)可能是一种潜在的抗轮状病毒药物。因此，我们使用细胞和小鼠模型来研究CsA作为一种抗轮状病毒药物的免疫学安全性和有效性。我们发现，在病毒感染前、期间和感染后，CsA处理的HT-29细胞有效地抑制了Wa株RV的复制，并在HT-29细胞系模型中恢复了干扰素-β的表达。对潜在机制的探索表明，CsA促进干扰素调节因子-5(IRF-5)的表达(I型干扰素信号通路的关键正向调节因子)，但不促进IRF-1、IRF-3或IRF-7的表达。此外，CsA可抑制干扰素-α/β的关键负调控因子SOCS-1的表达，但不能抑制SOCS-2或SOCS-3的表达。在RV感染的新生小鼠模型中，通过评估抗原清除和肠道组织病理变化，证实了CsA的抗病毒作用。此外，在环孢素A治疗组和赋形剂治疗组之间也没有观察到T细胞频率或增殖的差异。因此，我们在体外和体内的研究结果都表明，CsA通过调节干扰素信号通路中关键调节因子的表达，促进RV宿主细胞基于I型干扰素的天然免疫。这些发现表明，CsA可能是开发一种新的抗RV策略的有用候选药物，尽管CsA在RV诱导的腹泻中的进一步评估和特征是有必要的。
Rotavirus (RV) is the most common cause of severe diarrhea among infants and young children. Currently, there is no specific drug available against rotavirus, largely due to the lack of an ideal target molecule which has hampered drug development. Our previous studies have revealed that cyclosporin A (CsA) might be potentially useful as an anti-RV drug. We therefore used both cellular and mouse models to study the immunological safety and effectiveness of CsA as an anti-RV drug. We found that CsA treatment of HT-29 cells before, during, and after viral infection efficiently inhibited Wa strain RV replication and restored IFN-β expression in a HT-29 cell line model. Exploring the underlying mechanisms showed that CsA promoted Interferon Regulatory Factor-5 (IRF-5) expression (a key positive regulator of the type I IFN signaling pathway), but not IRF-1, IRF-3, or IRF-7. Additionally, CsA inhibited SOCS-1 expression (the key negative regulator of IFN-α/β), but not SOCS-2 or SOCS-3. The antiviral effect of CsA was confirmed in an RV-infected neonatal mouse model by evaluation of antigen clearance and assessment of changes in intestinal tissue pathology. Also, no differences in T cell frequency or proliferation between the CsA- and vehicle-treated groups were observed. Thus, both our in vitro and in vivo findings suggest that CsA, through modulating the expression of key regulators in IFN signaling pathway, promote type I IFN-based intracellular innate immunity in RV host cells. These findings suggest that CsA may be a useful candidate to develop a new anti-RV strategy, although further evaluation and characterization of CsA on RV-induced diarrhea are warranted.
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影响因子：
3.1
作者：
Min, Bok-Soon;Noh, Yoon-Ju;Ahn, Byung-Yoon
通讯作者：
Ahn, Byung-Yoon
影响因子：
2.3
作者：
Chaplin, PJ;Entrican, G;Collins, RA
通讯作者：
Collins, RA
影响因子：
2.6
作者：
Garosi, L;McConnell, JF;Schatzberg, SJ
通讯作者：
Schatzberg, SJ
影响因子：
5.4
作者：
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通讯作者：
Einerhand, AWC
影响因子：
5.4
作者：
Barro, Mario;Patton, John T.
通讯作者：
Patton, John T.