[转移帖]Nat Immunol.：揭示干扰素抗病毒新机制——“外体”

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   原帖由ipsvirus于2013-7-8 14:14 发于老论坛

    上海医学院基础医学院教育部、卫生部医学分子病毒学重点实验室主任袁正宏研究员率领课题组，历经4年多潜心研究和探索，终于发现，“干扰素-a”通过促使细胞分泌的exosomes（外体）所携带的具有抗病毒作用的蛋白和核酸等分子，在细胞间传递后发挥抗病毒作用的新机制。有业内人士对记者表示，该发现对今后开发治疗慢性乙肝和其它病毒感染性疾病的新药有重大意义。

     这项新的研究成果发表在国际权威期刊《自然·免疫学》（Nature Immunology）上，引起世界同行关注。据透露，该课题组已将有关“干扰素-a”处理细胞分泌“外体”用于抗病毒治疗的项目申请国家专利，相关的临床前研究工作也正紧锣密鼓的进行中。

     据了解，干扰素是一组有多种功能的活性蛋白质，具有广泛的抗病毒作用，其中“干扰素-a”是国际权威组织食品和药物管理局最早批准的用于治疗肝炎的抗病毒药物。“外体”是一种由细胞主动分泌出的微囊结构，大小介于30至100纳米间。“外体”在细胞间的通讯中发挥重要作用，不仅参与多种生理、病理过程，还在不同条件下，对于肿瘤发生、发展起到或促进，或抑制的作用。

     据介绍，肝脏中的肝细胞是乙肝病毒活动、复制的唯一场所；而肝脏中的非实质细胞则连接、支撑肝细胞。袁正宏课题组经研究发现，肝脏的肝非实质细胞中的肝窦内皮细胞和巨噬细胞会分泌“外体”，在“干扰素-a”的诱导下，通过特定方式转运到易受到病毒感染的肝细胞中后，“外体”会“拼命”抵抗或清除乙肝病毒感染。



      此外研究人员还在小鼠上验证了“外体”同样对鼠肝炎病毒A59和腺病毒也发挥抗病毒作用。

     在应对病的的变异、耐药性方面，这些存在于“外体”中的抗病毒分子好比“免疫军工厂”制造出的一种“火力十足”的“先进武器”，迫使病毒无法变异或产生耐药性。由此，“干扰素-a”诱导细胞分泌的“外体”，具有广谱、高效的抗病毒作用。

     袁正宏课题组还发现，如果阻断小鼠模型中“外体”有效释放，其肝炎严重程度则会明显加重；因此，利用“外体”治疗一些由病毒引起的感染是有可能的。

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Gastroenterology. 2015 Feb;148(2):392-402.e13. doi: 10.1053/j.gastro.2014.10.040. Epub 2014 Nov 4.
Hepatitis C virus infection induces autocrine interferon signaling by human liver endothelial cells and release ofexosomes, which inhibits viral replication.Giugliano S,  Kriss M,  Golden-Mason L,  Dobrinskikh E,  Stone AE, Soto-Gutierrez A,  Mitchell A,  Khetani SR, Yamane D, Stoddard M,  Li H,  Shaw GM,  Edwards MG,  Lemon SM,  Gale M Jr,  Shah VH,  Rosen HR


AbstractBACKGROUND & AIMS:

Liver sinusoidal endothelial cells (LSECs) make up a large proportion of the nonparenchymal cells in the liver. LSECs are involved in induction of immune tolerance, but little is known about their functions during hepatitis C virus (HCV) infection.

METHODS:

Primary human LSECs (HLSECs) and immortalized liver endothelial cells (TMNK-1) were exposed to various forms of HCV, including full-length transmitted/founder virus, sucrose-purified Japanese fulminant hepatitis-1 (JFH-1), a virus encoding a luciferase reporter, and the HCV-specific pathogen-associated molecular pattern molecules. Cells were analyzed by confocal immunofluorescence, immunohistochemical, and polymerase chain reaction assays.

RESULTS:

HLSECs internalized HCV, independent of cell-cell contacts; HCV RNA was translated but not replicated. Through pattern recognition receptors (Toll-like receptor 7 and retinoic acid-inducible gene 1), HCV RNA induced consistent and broad transcription of multiple interferons (IFNs); supernatants from primary HLSECs transfected with HCV-specific pathogen-associated molecular pattern molecules increased induction of IFNs andIFN-stimulated genes in HLSECs. Recombinant type I and type III IFNs strongly up-regulated HLSEC transcription of IFN λ3 (IFNL3) and viperin (RSAD2), which inhibit replication of HCV. Compared with CD8(+) T cells, HLSECs suppressed HCV replication within Huh7.5.1 cells, also inducingIFN-stimulated genes in co-culture. Conditioned media from IFN-stimulated HLSECs induced expression of antiviral genes by uninfected primary human hepatocytes. Exosomes, derived from HLSECs after stimulation with either type I or type III IFNs, controlled HCV replication in a dose-dependent manner.

CONCLUSIONS:

Cultured HLSECs produce factors that mediate immunity against HCV. HLSECs induce self-amplifying IFN-mediated responses and release of exosomes with antiviral activity.

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exosomes在这几年还是挺火的。感染的免疫细胞可以通过分泌胞内体，将一些抗病毒成分，比如蛋白分子，核酸分子等带到组织细胞中，来发挥抗病毒作用。

还有很多文章报道了类似机制。

Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):E4991-6. doi: 10.1073/pnas.1419338111. Epub 2014 Nov 3.

Cells infected with herpes simplex virus 1 export to uninfected cells exosomes containing STING, viral mRNAs, and microRNAs.
Kalamvoki M1, Du T1, Roizman B2.

Abstract
STING (stimulator of IFN genes) activates the IFN-dependent innate immune response to infection on sensing the presence of DNA in cytosol. The quantity of STING accumulating in cultured cells varies; it is relatively high in some cell lines [e.g., HEp-2, human embryonic lung fibroblasts (HEL), and HeLa] and low in others (e.g., Vero cells). In a preceding publication we reported that STING was stable in four cell lines infected with herpes simplex virus 1 and that it was actively stabilized in at least two cell lines derived from human cancers. In this report we show that STING is exported from HEp-2 cells to Vero cells along with virions, viral mRNAs, microRNAs, and the exosome marker protein CD9. The virions and exosomes copurified. The quantity of STING and CD9 exported from one cell line to another was inoculum-size-dependent and reflected the levels of STING and CD9 accumulating in the cells in which the virus inoculum was made. The export of STING, an innate immune sensor, and of viral mRNAs whose major role may be in silencing viral genes in latently infected neurons, suggests that the virus has evolved mechanisms that curtail rather than foster the spread of infection under certain conditions.

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Exosomes mediate the cell-to-cell transmission of IFN-α-induced antiviral activity

Jianhua Li, Kuancheng Liu, Yang Liu, Yan Xu, Fei Zhang, Huijuan Yang, Jiangxia Liu, Tingting Pan, Jieliang Chen, Min Wu, Xiaohui Zhou        & Zhenghong Yuan

The cell-to-cell transmission of viral resistance is a potential mechanism for amplifying the interferon-induced antiviral response. In this study, we report that interferon-α (IFN-α) induced the transfer of resistance to hepatitis B virus (HBV) from nonpermissive liver nonparenchymal cells (LNPCs) to permissive hepatocytes via exosomes. Exosomes from IFN-α-treated LNPCs were rich in molecules with antiviral activity. Moreover, exosomes from LNPCs were internalized by hepatocytes, which mediated the intercellular transfer of antiviral molecules. Finally, we found that exosomes also contributed to the antiviral response of IFN-α to mouse hepatitis virus A59 and adenovirus in mice. Thus, we propose an antiviral mechanism of IFN-α activity that involves the induction and intercellular transfer of antiviral molecules via exosomes.

http://www.nature.com/ni/journal ... mentary-information