Cell Host & Microbe：双重重大发现详解解读，抗病毒与炎症小体激活机制

2015-04-10 佚名生物谷

先天免疫系统能够快速识别外界病原体物质以及自身的危险信号进而提供有效的保护。在病毒入侵过程中，其病毒携带的核酸物质被认为是一种典型的PAMP（Pathogen Associated Molecular Pattern）信号，其中包括双链RNA，富含尿嘧啶的单链RNA以及存在于胞浆中的基因组DNA。PAMP的识别依赖于细胞膜或细胞内部一系列模式识别受体（Pattern Rcognition

先天免疫系统能够快速识别外界病原体物质以及自身的危险信号进而提供有效的保护。在病毒入侵过程中，其病毒携带的核酸物质被认为是一种典型的PAMP（Pathogen Associated Molecular Pattern）信号，其中包括双链RNA，富含尿嘧啶的单链RNA以及存在于胞浆中的基因组DNA。PAMP的识别依赖于细胞膜或细胞内部一系列模式识别受体（Pattern Rcognition Receptor，PRR），之前已经有许多文章介绍过模式识别受体的相关知识，在此仅简要复述有关核酸识别受体的内容。TLRs（Toll Like Receptors）：包括可以识别dsRNA的TLR3，识别ssRNA的TLR7/8以及识别dsDNA的TLR9；胞浆中存在的识别DNA的感受元件：包括cGAS等在内；胞浆中识别dsRNA的感受元件：包括RIG-I，MDA-5等。

除此之外，病毒入侵还可以激活免疫小体（inflammasome）。简单来说，免疫小体是由三种蛋白质组成的复合体。典型的NLRP3炎症小体包括NLRP3，ASC以及pro-caspase1。炎症小体的激活依赖两步信号：1.prime信号：即NF-kB的激活导致pro-caspase 1与pro-IL-1b的表达；2. Host damage 信号：即炎症小体的形成与caspase1的激活进而导致的IL-1b的成熟与分泌。尽管目前已经有实验表明多种病毒类型均可以激活炎症小体，但其具体的激活机制目前仍不清楚。

最近，来自美国克利夫兰lerner研究所的炎症研究学系的Robert H. Silverman课题组在cell hostµbe文章中报道了他们对于一类RNA酶：RNase L，在病毒侵染激活免疫小体机制的最新研究成果。

首先要向大家介绍这类RNA酶。RNase L在受到病毒侵染的细胞内部活化程度较高。具体原因为：病毒侵染细胞内部IFN水平较高，而IFN能够诱导OAS（一类寡聚腺嘌呤合成酶）的表达，OAS进而合成2'-5'连接的寡聚核苷酸链。在静息状态下，Rnase L为单体状态，而在受到寡聚核苷酸链的刺激下则会发生二聚化，从而得到激活。在抗病毒过程中，Rnase L能够特异性识别polyU-polyA或polyU-polyU特征的ssRNA序列并在其下游进行切割。有研究已经发现RNase L能够造成细胞的自噬效应与细胞凋亡效应，这些都对抗病毒免疫反应有所贡献，而接下来作者希望了解它对炎症小体的功能的影响。

首先，作者构建了RNase L敲除小鼠，然后向野生型小鼠与突变体小鼠同时感染鼠源的流感病毒。15天后，作者发现野生小鼠有80%的存活率，而相比之下突变小鼠只有34%的存活率。然而，两组小鼠在体重方面并没有明显差异。之后，作者比较了两组小鼠在感染病毒两天后肺组织及流出液中IL-1b的分泌情况，结果显示：突变体小鼠的各组织IL-1b的分泌量相比野生型只有90%与75%的水平。感染七天以后，突变体小鼠肺部的病毒载量相比于野生型要高4倍左右。以上实验结果说明了Rnase L能够影响IL-1b的成熟以及小鼠的抗病毒能力。

由于IL-1b的成熟依赖于免疫小体的激活，作者希望了解Rnase L在此过程中酒精扮演了怎样的角色。因此，作者分离了野生型与突变体小鼠的骨髓树突状细胞（BMDC）进行体外刺激：LPS prime&病毒感染。实验结果显示，相比于野生型，突变体BMDC在刺激条件下IL-1b的分泌量下降了80%。同时，TNF-a代替LPS进行prime也得到了相似的结果。ATP是一类验证小体的激活剂，作者利用ATP代替病毒进行刺激，结果令人意外：在ATP刺激情形下，野生型与突变体小组并没有明显差异。这一实验结果说明Rnase L并不是一个广谱的炎症小体调节分子，而是有可能仅与病毒侵染有关。

之后，作者比较了仅prime以及prime加后续病毒侵染条件下pro-IL1b以及成熟IL-1b的水平。通过系统的ELISA以及WB分析方法，作者发现野生型与突变体BMDC在接受LPS刺激后其pro-IL1b的表达量差异不明显，然而在进一步接受病毒感染之后，野生型BMDC表现出了大量的IL-1b的切割与分泌，而突变体组仅有少量的切割与分泌。这一实验结果说明Rnase L对炎症小体的影响在第二信号阶段。

之后，作者利用RIG-I以及MAVS突变体进行体外刺激实验，结果显示MAVS，而非RIG-I，对于IL-1b的成熟具有影响。

为了进一步研究Rnase L在这一过程中的功能，作者利用其特异性的激活剂：2'-5'寡聚腺嘌呤直接刺激野生型与突变体的BMDC。经过转染之后，作者发现野生型BMDC内部RNAse L活性提高，同时伴随着IL-1b的成熟与分泌，而在突变体中则没有这一现象。这一结果暗示了IL-1b的成熟依赖于Rnase L的酶切活性。

之后，作者希望了解是否是Rnase L的酶切产物激活了炎症小体，因此他们分别将完整的流感病毒基因组或者经过Rnase L酶切处理后的产物转染到野生型与突变体BMDC中。实验结果显示：相比于转染完整的基因组序列，酶切产物能够引起更高的IL-1b的分泌；另一方面，如果仅比较相同类型的刺激方式，完整的基因组序列在野生型BMDC中能够引起比突变体更高的IL-1b的分泌，然而这一差异在转染切割后产物的情况下变得不再明显。同时，他们利用胞浆中的宿主RNA进行实验得到了相似的结果。这一结果进一步肯定了Rnase L 的酶切活性对于IL-1b成熟的影响。那么酶切产物的什么特征使得它能够相比于完整的基因组序列具有更强的激活能力呢？作者通过PNK将酶切产物的2'-3'环化2磷酸切除后发现其诱导IL-1b的能力明显下降，这一实验说明这一官能团对于其激活下游的信号十分必要。

接下来，作者通过比较不同类型的突变体（Rnase L-/-, ASC-/-, NLRP3-/-），发现即使酶切后的核酸片段引导IL-1b的产生也需要ASC以及NLRP3的存在。这一结果说明Rnase L作用在炎症小体的上游。之后，作者通过体外突变的方式（失活突变）证明了RNAse L的酶切活性对于其诱导炎症小体激活具有重要作用。

最后，作者希望找到直接识别Rnase L酶切产物的分子。作者首先通过RNAi的方式发现一类RNA解旋酶，同时也是dsRNA的感受元件的DDX1能够影响IL-1b的成熟。进一步的生化实验证明其在受刺激情况下能够与MAVS以及NLRP3形成三元复合体。

综上，作者利用遗传，生化等手段系统地证明了Rnase L在抗病毒免疫小体激活方面的作用。编者认为，这篇文章有两方面的重大突破：1. 发现了抗病毒先天免疫的新机制；2.发现了炎症小体的另一激活方式。而这两个都是免疫学研究中的十分重要而热点的问题。

原始出处：

Arindam Chakrabarti1, 5, Shuvojit Banerjee1, 5, Luigi Franchi2, 3, Yueh-Ming Loo4, Michael Gale Jr.4, Gabriel Núñez2, Robert H. Silverman1.RNase L Activates the NLRP3 Inflammasome during Viral Infections.Cell Host & Microbe, April 8, 2015, 17(4):466-477. doi:10.1016/j.chom.2015.02.010

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2015-06-18 维他命

#CEL#

22 0
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2015-07-15 zhaozhouchifen

#Cell#

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2015-07-11 xjy02

#Micro#

26 0
[GetPortalCommentsPageByObjectIdResponse(id=1959325, encodeId=e6201959325c2, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Jun 18 12:58:00 CST 2015, time=2015-06-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1869074, encodeId=d37b18690e42c, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Wed Jul 15 20:58:00 CST 2015, time=2015-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2084119, encodeId=4e3f20841196a, content=<a href='/topic/show?id=61f411e013b' target=_blank style='color:#2F92EE;'>#Micro#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11701, encryptionId=61f411e013b, topicName=Micro)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, createdName=xjy02, createdTime=Sat Jul 11 06:58:00 CST 2015, time=2015-07-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1857344, encodeId=d1c2185e34425, content=<a href='/topic/show?id=3f48525849' target=_blank style='color:#2F92EE;'>#CRO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5258, encryptionId=3f48525849, topicName=CRO)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c30265, createdName=jiafufeng@yaho, createdTime=Wed Mar 23 01:58:00 CST 2016, time=2016-03-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1945435, encodeId=51f51945435e2, content=<a href='/topic/show?id=41ef95e62c5' target=_blank style='color:#2F92EE;'>#重大发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=95762, encryptionId=41ef95e62c5, topicName=重大发现)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6393434, createdName=ailian1202, createdTime=Thu Jun 25 22:58:00 CST 2015, time=2015-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1292325, encodeId=f3931292325a8, content=<a href='/topic/show?id=a3b4554e19d' target=_blank style='color:#2F92EE;'>#抗病毒#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=55471, encryptionId=a3b4554e19d, topicName=抗病毒)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=52c7237, createdName=yahu, createdTime=Sun Apr 12 03:58:00 CST 2015, time=2015-04-12, status=1, ipAttribution=)]
2016-03-23 jiafufeng@yaho

#CRO#

37 0
[GetPortalCommentsPageByObjectIdResponse(id=1959325, encodeId=e6201959325c2, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Jun 18 12:58:00 CST 2015, time=2015-06-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1869074, encodeId=d37b18690e42c, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Wed Jul 15 20:58:00 CST 2015, time=2015-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2084119, encodeId=4e3f20841196a, content=<a href='/topic/show?id=61f411e013b' target=_blank style='color:#2F92EE;'>#Micro#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11701, encryptionId=61f411e013b, topicName=Micro)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, createdName=xjy02, createdTime=Sat Jul 11 06:58:00 CST 2015, time=2015-07-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1857344, encodeId=d1c2185e34425, content=<a href='/topic/show?id=3f48525849' target=_blank style='color:#2F92EE;'>#CRO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5258, encryptionId=3f48525849, topicName=CRO)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c30265, createdName=jiafufeng@yaho, createdTime=Wed Mar 23 01:58:00 CST 2016, time=2016-03-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1945435, encodeId=51f51945435e2, content=<a href='/topic/show?id=41ef95e62c5' target=_blank style='color:#2F92EE;'>#重大发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=95762, encryptionId=41ef95e62c5, topicName=重大发现)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6393434, createdName=ailian1202, createdTime=Thu Jun 25 22:58:00 CST 2015, time=2015-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1292325, encodeId=f3931292325a8, content=<a href='/topic/show?id=a3b4554e19d' target=_blank style='color:#2F92EE;'>#抗病毒#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=55471, encryptionId=a3b4554e19d, topicName=抗病毒)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=52c7237, createdName=yahu, createdTime=Sun Apr 12 03:58:00 CST 2015, time=2015-04-12, status=1, ipAttribution=)]
2015-06-25 ailian1202

#重大发现#

32 0
[GetPortalCommentsPageByObjectIdResponse(id=1959325, encodeId=e6201959325c2, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=22, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Jun 18 12:58:00 CST 2015, time=2015-06-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1869074, encodeId=d37b18690e42c, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Wed Jul 15 20:58:00 CST 2015, time=2015-07-15, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2084119, encodeId=4e3f20841196a, content=<a href='/topic/show?id=61f411e013b' target=_blank style='color:#2F92EE;'>#Micro#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11701, encryptionId=61f411e013b, topicName=Micro)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, createdName=xjy02, createdTime=Sat Jul 11 06:58:00 CST 2015, time=2015-07-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1857344, encodeId=d1c2185e34425, content=<a href='/topic/show?id=3f48525849' target=_blank style='color:#2F92EE;'>#CRO#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5258, encryptionId=3f48525849, topicName=CRO)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c30265, createdName=jiafufeng@yaho, createdTime=Wed Mar 23 01:58:00 CST 2016, time=2016-03-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1945435, encodeId=51f51945435e2, content=<a href='/topic/show?id=41ef95e62c5' target=_blank style='color:#2F92EE;'>#重大发现#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=95762, encryptionId=41ef95e62c5, topicName=重大发现)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=6393434, createdName=ailian1202, createdTime=Thu Jun 25 22:58:00 CST 2015, time=2015-06-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1292325, encodeId=f3931292325a8, content=<a href='/topic/show?id=a3b4554e19d' target=_blank style='color:#2F92EE;'>#抗病毒#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=29, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=55471, encryptionId=a3b4554e19d, topicName=抗病毒)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=52c7237, createdName=yahu, createdTime=Sun Apr 12 03:58:00 CST 2015, time=2015-04-12, status=1, ipAttribution=)]
2015-04-12 yahu

#抗病毒#

29 0

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