《病毒学期刊》：一皮层蛋白能够抑制β干扰素产生

来自中科院武汉病毒研究所。安徽医科大学的研究人员首次发现HSV-1皮层蛋白US11能够抑制β干扰素的产生,是一个新的拮抗RIG-I样模式识别受体（RLR）介导的天然免疫信号通路的HSV-1蛋白。这-I型单纯疱疹病毒拮抗宿主天然免疫反应机制新发现发表于国际病毒学核心刊物Journal of Virology上。     

线粒体抗病毒信号蛋白(MAVS)在宿主天然免疫信号通路中的调节作用

线粒体抗病毒信号蛋白(MAVS)作为一种接头蛋白在调节宿主天然免疫信号通路过程中扮演重要角色．Toll样受体(TLR)和RIG-Ⅰ样受体(RLR)等细胞模式识别受体识别入侵的病原体并将信号传递给MAVS,MAVS通过刺激下游的TBK1复合体和IKK复合体分别活化NF-κB和IRF3等信号通路,进而激活干扰素α／β表达,诱发细胞内抗感染天然免疫反应．MAVS除定位线粒体外,也可定位于过氧化物酶体上．MAVS在细胞内的不同定位决定了其在早期快速和持续性抗病毒天然免疫中的不同调节机制．MAVS只有同时定位在过氧化物酶体和线粒体上才可诱导干扰素刺激基因(ISG)快速且稳定地表达．本文通过对MAVS的发现、结构、细胞定位及其在天然免疫信号通路中的调控机制等最新进展进行综述,以期揭示MAVS蛋白在细胞内天然免疫信号通路中的重要调节作用,为研究病毒逃逸宿主天然免疫的机制和研究新型抗病毒免疫治疗策略提供新思路．     

人类冠状病毒调节宿主抗病毒天然免疫分子机制

SARS冠状病毒和正在全球流行的猪源H1N1型流感病毒等人类新发呼吸道病毒对人类生命健康构成严重威胁.人类重要呼吸道病毒与宿主抗病毒天然免疫的关系是近年来研究热点.SARS冠状病毒等很多RNA病毒能够编码某种蛋白质,抑制干扰素表达以及干扰素介导的抗病毒信号通路.人类冠状病毒木瓜样蛋白酶(papain-like protease,PLP)利用其自身去泛素化酶(DUB)活性,使干扰素表达通路中重要调节蛋白发生去泛素化,从而抑制干扰素信号传导.同时,PLP蛋白酶通过阻碍干扰素表达信号通路中最新发现的重要调节蛋白ERIS(也称MITA/STING)二聚化,使其失活并丧失激活干扰素通路的功能,这些发现对于阐明人类重要呼吸道病毒对宿主细胞抗病毒天然免疫反应的调节作用及其机制具有重要意义,为人类新发病毒致病机理、免疫防治以及抗病毒药物研究提供新的思路.     

Toll样受体家族与天然免疫

Toll受体是近年来发现的跨膜信号传递受体蛋白,它在哺乳动物,昆虫及植物的信号转导通路中有类似的作用。TLR可选择性识别病原微生物而启动天然免疫,因此,它在宿主的天然免疫中具有重要作用。本文主要对TLR家族的研究进展及其在天然免疫中的作用加以综述。     

轮状病毒非结构蛋白NSP1与宿主的相互作用

轮状病毒（rotavirus,RV）非结构蛋白1（nonstructural protein 1,NSP1）是轮状病毒逃避宿主天然免疫应答的关键蛋白质。它可以与干扰素调控因子家族（interferon regulatoryfactor family,IRFF）的共同区域结合,阻断干扰素表达的信号通路,降低宿主细胞I型干扰素（type I interferon,IFN-I）的表达,从而抑制宿主天然抗病毒免疫机制的建立。因此,NSP1被认为是轮状病毒的一种重要毒力因子。本文综述了近年来轮状病毒NSP1与宿主相互作用的研究进展。     

重组腺相关病毒载体诱导的天然免疫反应及机制

重组腺相关病毒(rAAV)已成为基因治疗领域应用最广泛的载体之一。临床前研究显示其具有很高的安全性,但人体免疫毒性仍是制约其临床疗效的关键,因此有关rAAV免疫机制的研究成为近期热点。尽管天然免疫在获得性免疫反应中发挥重要作用,但与rAAV有关的天然免疫研究过去一直未被重视。直到最近,才确认有至少3种人体细胞(树突状细胞、巨噬细胞和内皮细胞)参与了rAAV的天然免疫,作用机制为可识别载体基因组的TLR9或病毒衣壳TLR2所介导,NF-κB或干扰素调节因子(IRFs)信号通路被激活,导致各种炎性因子及I型干扰素的大量表达。自身互补型rAAV诱导的TLR9依赖性天然免疫较单链rAAV更为强烈。本文重点对近期发现的激活天然免疫反应的宿主与rAAV的相互作用、涉及的信号通路、天然免疫对获得性免疫以及转基因表达的影响进行综述。     

第二信使神经酰胺

第二信使神经酰胺丁振华（第一军医大学基础部,广州５１０５１５）关键词第二信使神经酰胺鞘磷脂酶１９９５年,Ｂｏｕｃｈｅｒ及其同事发现,在原代培养的小鼠脾Ｔ淋巴细胞中,ＣＤ２８的信号传导能够通过鞘磷脂（ｓｐｈｉｎｇｏｍｙｌｉｎ）通路而活化核因子ＮＦ－κＢ...     

病毒感染调控JAK/STAT信号通路：逃避与利用

JAK/STAT信号通路是天然免疫过程中一条关键通路，参与了干扰素信号传递入细胞核的过程。研究表明，病毒通过逃避甚至利用JAK/STAT信号通路，对抗干扰素系统的抗病毒效果。在此过程中，调控干扰素受体蛋白、减少JAK和STAT蛋白的数量、阻碍STAT的磷酸化或核易位，又或是上调SOCS家族蛋白都是病毒常用的手段。本文重点介绍了病毒调控JAK/STAT信号通路的过程，为病毒致病机理的研究和抗病毒药物的设计提供了理论基础。     

Hippo信号通路调控天然免疫的研究进展

Hippo信号通路在细胞的增殖、分化以及凋亡等方面扮演着重要的角色.同时Hippo信号通路又是响应多种环境条件的效应器,如葡萄糖饥饿、细胞密度、病原体感染以及热激等.近年来的研究发现, Hippo信号通路在天然免疫中具有重要的作用.更为重要的是, Hippo信号通路在调控天然免疫过程中,存在核心蛋白相互不依赖的特征, YAP(yes-associated protein)对天然免疫的调节往往独立于上游激酶的调控.同时,在不同的组织和物种中YAP的抵抗病原体的作用也存在差异.本文从Hippo信号通路的演化、调控关系以及Hippo信号通路在抗病毒和抗细菌中的作用,阐述了Hippo信号通路与天然免疫的关系.     

RLRs介导的抗鲤春病毒血症病毒作用研究进展

鲤春病毒血症病毒(SVCV)是水生动物病毒中重要的病原体,常引起鲤科鱼类疾病暴发。近些年研究发现,维甲酸诱导基因I样受体家族(RLRs)信号通路在SVCV免疫过程中起到重要的作用。主要功能是在识别病原体相关模式,激活下游信号分子,诱导天然免疫的产生,以及控制病毒的早期复制。当病毒进入机体时会形成病毒-RLRs-IFN互联反馈回路,RLRs相关基因识别SVCV的RNA,最终引起Ⅰ型干扰素(IFN-I)表达量升高,并且RLRs族内成员相互作用增强抗病毒作用。RLRs不仅可以活化天然免疫信号通路,还可增强适应性免疫效应,在控制病毒感染过程中发挥重要作用。介绍RLRs家族,RLRs抗病毒信号调控因子,干扰素诱导的鱼类Mx (myxovirus resistant)蛋白对鲤春病毒血症病毒的抑制作用。     

The mechanism of STING autoinhibition and activation

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MITA/STING: A central and multifaceted mediator in innate immune response

The recognition of nucleic acids is a general strategy used by the host to detect invading pathogens. Many studies have established that MITA/STING is a central component in the innate immune response to cytosolic DNA and RNA derived from pathogens. MITA can act both as a direct sensor of cyclic dinucleotides (CDNs) and as an adaptor for the recruitment of downstream signaling components. In both roles, MITA is part of signaling cascades that orchestrate innate immune defenses against various pathogens, including viruses, bacteria and parasites. Here, we highlight recent studies that have uncovered the molecular mechanisms of MITA-mediated signal transduction and regulation, and discuss some notable issues that remain elusive.     

Cyclic dinucleotides at the forefront of innate immunity

Cyclic dinucleotides (CDNs) have emerged as ubiquitous signaling molecules in all domains of life. In eukaryotes, CDN signaling systems are evolutionarily ancient and have developed to sense and respond to pathogen infection. On the other hand, dysregulation of these pathways has been implicated in the pathogenesis of autoimmune diseases. Thus, CDNs have garnered major interest over recent years for their ability to elicit potent immune responses in the eukaryotic host. Similarly, ancestral CDN-based signaling systems also appear to confer immunological protection against infection in prokaryotes. Therefore, a better understanding of the host processes regulated by CDNs will be of tremendous value in many areas of research. Here, we aim to review the latest discoveries and recent trends in CDN research with a particular focus on the molecular mechanisms by which these small molecules mediate innate immunity.     

The catalytic mechanism of cyclic GMP‐AMP synthase (cGAS) and implications for innate immunity and inhibition

Cyclic GMP‐AMP synthase (cGAS) is activated by ds‐DNA binding to produce the secondary messenger 2′,3′‐cGAMP. cGAS is an important control point in the innate immune response; dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology. We report here the structure of cGAS with dinucleotides and small molecule inhibitors, and kinetic studies of the cGAS mechanism. Our structural work supports the understanding of how ds‐DNA activates cGAS, suggesting a site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. Mechanistic studies of cGAS provide the first kinetic constants for 2′,3′‐cGAMP formation, and interestingly, describe a catalytic mechanism where 2′,3′‐cGAMP may be a minor product of cGAS compared with linear nucleotides.     

The N-Terminal Domain of cGAS Determines Preferential Association with Centromeric DNA and Innate Immune Activation in the Nucleus

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Inclusion of cGAMP within virus‐like particle vaccines enhances their immunogenicity

Cyclic GMP‐AMP (cGAMP) is an immunostimulatory molecule produced by cGAS that activates STING. cGAMP is an adjuvant when administered alongside antigens. cGAMP is also incorporated into enveloped virus particles during budding. Here, we investigate whether inclusion of cGAMP within viral vaccine vectors enhances their immunogenicity. We immunise mice with virus‐like particles (VLPs) containing HIV‐1 Gag and the vesicular stomatitis virus envelope glycoprotein G (VSV‐G). cGAMP loading of VLPs augments CD4 and CD8 T‐cell responses. It also increases VLP‐ and VSV‐G‐specific antibody titres in a STING‐dependent manner and enhances virus neutralisation, accompanied by increased numbers of T follicular helper cells. Vaccination with cGAMP‐loaded VLPs containing haemagglutinin induces high titres of influenza A virus neutralising antibodies and confers protection upon virus challenge. This requires cGAMP inclusion within VLPs and is achieved at markedly reduced cGAMP doses. Similarly, cGAMP loading of VLPs containing the SARS‐CoV‐2 Spike protein enhances Spike‐specific antibody titres. cGAMP‐loaded VLPs are thus an attractive platform for vaccination.     

Unmasking immune sensing of retroviruses: Interplay between innate sensors and host effectors

Retroviruses can selectively trigger an array of innate immune responses through various PRR. The identification and the characterization of the molecular basis of retroviral DNA sensing by the DNA sensors IFI16 and cGAS has been one of the most exciting developments in viral immunology in recent years. DNA sensing by these cytosolic sensors not only leads to the initiation of the type I interferon (IFN) antiviral response and the induction of the inflammatory response, but also triggers cell death mechanisms including pyroptosis and apoptosis in retrovirus-infected cells, thereby providing important insights into the pathophysiology of chronic retroviral infection. Host restriction factors such as SAMHD1 and Trex1 play important roles in regulating innate immune sensing, and have led to the idea that innate immune defense and host restriction actually converge at different levels to determine the outcome of retroviral infection. In this review, we discuss the sensing of retroviruses by cytosolic DNA sensors, the relevance of host factors during retroviral infection, and the interplay between host factors and the innate antiviral response in different cell types, within the context of two human pathogenic retroviruses – human immunodeficiency virus (HIV-1) and human T cell-leukemia virus type I (HTLV-1).