MicroRNA调控固有免疫应答的分子机制

MicroRNA（miRNA）是近几年继siRNA之后非编码RNA研究的又一热点．它通过与靶mRNA的特异性结合,在转录后水平上对基因表达进行调控．研究表明,miRNA可能参与脊椎动物固有免疫应答的多个环节．在病原微生物感染时,它们不仅成为重要的固有免疫受体活化后的信号调节分子,而且能够直接干扰病毒复制而发挥抗病毒效应．miRNA可能与经典的固有免疫应答体系共同组成机体抵御病原微生物入侵的“第一道防线”．同时,病原微生物,特别是病毒还可以通过自己编码miRNA或者改变宿主细胞miRNA表达谱直接或间接地干扰很多宿主免疫相关基因的表达,实现逃逸机体免疫清除的目的．因此,miRNA水平的相瓦作用可能是病原微生物与其宿丰展开免疫“博弈”的重要战场．     

病毒持续性感染难治愈的因素及对策

病毒持续性感染引起的病程多为慢性或反复发作,难以治愈,在部分患者甚至可引发肿瘤或自身免疫性疾病等,是严重危害人类健康及造成社会重大经济负担的常见病及多发病。持续性感染难以治愈的原因涉及病毒基因组与宿主细胞染色体整合,或以附加体的形式长期存在,以及病毒的酶或蛋白抑制机体的免疫应答等特性。此外,机体天然免疫或获得性免疫低下、免疫网络失调及感染微环境改变等,也是病毒建立并维持持续性感染的原因。本文根据持续性感染难以治愈的原因,从病原学与机体免疫应答两方面研讨一些对策,希望以此为切入点,为治疗持续性感染提供新思路与新策略。     

TANK结合激酶1在固有免疫应答中的作用及其泛素化调控

固有免疫系统通过模式识别受体识别病原微生物表面的病原相关分子模式启动固有免疫反应,经级联信号转导,激活下游转录因子NF-κB和干扰素调节因子IRFs,进而产生炎性细胞因子以及Ⅰ型干扰素,抵抗病原微生物感染。TANK结合激酶1 (TANK binding kinase 1,TBK1) 作为一个中心节点蛋白,参与多条固有免疫信号通路的传导,可同时激活NF-κB和IRFs,是机体抗感染过程中关键的蛋白激酶。TBK1的精准调控对维持机体免疫稳态、抵抗病原体入侵至关重要。文中综述了TBK1在固有免疫应答中的作用及其泛素化调控机制,以期为病原体感染及自身免疫病的临床治疗提供理论基础。     

猪肺炎支原体感染诱导的固有免疫应答研究进展

猪肺炎支原体是引起猪支原体肺炎的病原。由于缺乏成熟的猪肺炎支原体感染动物模型,使得猪肺炎支原体相关的抗感染免疫研究进展较为缓慢。本文从猪肺炎支原体感染后的炎症反应、固有免疫系统对猪肺炎支原体的识别、固有免疫细胞的作用、补体系统、抗菌肽、自噬以及细胞凋亡7个方面进行综述,旨在阐明固有免疫系统各组分在猪肺炎支原体感染中发挥的作用的研究进展,并对今后猪肺炎支原体感染的固有免疫应答研究的重点方向进行展望。     

抗病毒天然免疫研究

病毒是一种极具感染性和传染性的病原微生物．当病毒感染机体以后,机体会通过激活免疫系统来进行防御．高等哺乳动物的免疫系统分为两大类：适应性免疫系统和天然免疫系统．适应性免疫系统主要通过T淋巴细胞和B淋巴细胞特异性地识别入侵的病毒并将其清除．而天然免疫系统主要通过模式识别受体识别病毒的入侵,进而产生一系列的细胞因子抵抗病毒的入侵．其中,天然免疫系统作为抵御病毒入侵的第一道防线和激活后续适应性免疫的先决条件在整个抗病毒免疫反应中发挥着十分重要的作用．     

高致病性冠状病毒感染导致宿主免疫应答异常

近二十多年，全球范围内先后爆发了由严重急性呼吸综合征冠状病毒（severe acute respiratory syndrome coronavirus，SARS-CoV）、中东呼吸综合征冠状病毒（middle east respiratory syndrome coronavirus，MERS-CoV）和严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus 2，SARS-CoV-2）3种高致病性冠状病毒导致的疫情。这3种高致病性冠状病毒感染通常伴随着免疫系统功能失调，临床表现有淋巴细胞减少症、细胞因子风暴、急性呼吸系统窘迫综合征，甚至多器官衰竭而导致死亡。揭示高致病性冠状病毒在免疫应答中的作用机制，对于预防与控制冠状病毒感染具有重要意义。本文总结了SARS-CoV、MRES-CoV和SARS-CoV-2的进入机制和受体特征、固有免疫应答和适应性免疫应答失调方面的研究进展，强调了高致病性冠状病毒与宿主免疫应答之间的复杂相互作用，以期为防治冠状病毒感染提供参考。     

病毒特异性CD8+T细胞抗病毒免疫的研究进展

病毒利用宿主细胞核酸和蛋白质装置进行增殖,并与宿主细胞表面的受体结合,感染众多靶细胞c一旦建立感染,抗原呈递细胞通过内源性抗原呈递途径加工、呈递病毒抗原,激活机体免疫应答。病毒特异性免疫主要机制是细胞毒性T淋巴细胞作用,清除病原体和感染的靶细胞．同时CD8^ T细胞分化为记忆T细胞,介导再次免疫应答。     

肠道菌群参与宿主免疫应答的作用及机制研究进展

肠道菌群作为动物体内重要的组成部分,能够直接参与机体的免疫调控作用,促进机体免疫系统发育,维持正常免疫功能。同时,免疫系统对肠道菌群又有调控和制约作用。本文主要综述了肠道菌群的组成以及影响肠道菌群变化的因素,系统阐述了肠道菌群与疾病相互作用的机制,总结了肠道菌群在宿主感染与免疫应答中的作用,为开展肠道菌群参与机体免疫应答的机制方面的研究提供新的思路。     

树突状细胞在抗真菌感染免疫中的作用

近年来,随着广谱抗生素、抗肿瘤药物和免疫抑制剂等药物的广泛使用,免疫功能降低患者数量的增加,侵袭性真菌感染性疾病的发病率逐年升高。树突状细胞(Dendritic Cells,DCs)是已知功能最强的专职抗原提呈细胞,作为宿主固有免疫和适应性免疫的联系枢纽,DCs在病原微生物抗原的识别与呈递过程中发挥核心作用。研究证明,DCs可通过其细胞表面的多种受体有效识别病原真菌的抗原,并在诱导宿主免疫应答过程中发挥重要作用。本文将对树突状细胞分类及其在抗真菌感染免疫中的识别作用进行系统叙述。     

M细胞—启动粘膜免疫应答的人口

粘膜免疫系统是机体免疫系统的重要组成部分,外来抗原可选择性的M细胞相结合并被内吞入M细胞以诱导粘膜免疫应答或造成机体的感染。本文介绍了M细胞的结构、分化来源、生物学功能、与微生物感染的关系、及其在粘膜疫苗、药物传送中的应用。     

The fifth dimension of innate immunity

Innate immunity has evolved as a first line defense against invading pathogens. Cellular and humoral elements of the innate immune system detect infectious parasites, initiate inflammatory resistance reactions and finally contribute to the elimination of the invaders. Repeated attacks by pathogenic agents induce adaptive responses of the innate immune system. Typically, reapplication of pathogens provokes tolerance of the affected organism. However, also stimulatory effects of primary infections on subsequent innate immune responses have been observed. The present overview touches an undervalued aspect in the innate immune response: Its pronounced dependency on pathogen load. In addition to localization and timing of innate immune responses the pathogen dose dependency might be considered as a “fifth dimension of innate immunity”. Experimental results and literature data are presented proposing a hormetic reaction pattern of innate immune cells depending on the dose of pathogens.     

模式识别受体介导的天然免疫反应调节获得性免疫的机理

模式识别受体（PRR）的发现推动了免疫学领域的迅速发展.在近15年时间里,揭示了PRR启动的天然免疫反应机制及信号转导途径,并对天然免疫反应调节获得性免疫产生的机制进行了广泛研究.本文综述该领域一些新的重要发现,集中讨论病原体激活抗原递呈细胞的天然免疫反应调节淋巴细胞介导的抗原特异性获得性免疫机理,以及不同天然免疫途径在宿主抵抗感染和修复组织损伤中的作用,并讨论该领域尚未解决的重要问题.     

猪瘟病毒与宿主天然免疫系统的相互作用

猪瘟(Classical swine fever,CSF)是由猪瘟病毒(Classical swine fever virus,CSFV)感染引起的一种高度接触性传染病,临床上以出血综合征与免疫抑制为主要特征。它在多个国家流行,给中国乃至世界养猪业造成巨大的经济损失。研究表明,猪瘟病毒感染能够诱导宿主的天然免疫应答,也能通过影响天然免疫效应分子的表达来抑制宿主的天然免疫功能。本文将对猪瘟病毒感染与天然免疫应答及其免疫抑制的现象与机理进行综述。     

Herpes simplex viruses and induction of interferon responses

Herpes simplex viruses (HSV) are human pathogens responsible for a variety of diseases,including localized mucocutaneous lesions,encephalitis,and disseminated diseases.HSV infection leads to rapid induction of innate immune responses.A critical part of this host response is the type I IFN system including the induction of type I IFNs,IFN-mediated signaling and amplification of IFN response.This provides the host with immediate countermeasure during acute infection to limit initial viral replication and to facilitate an appropriate adaptive immune response.However,HSV has devised multiple strategies to evade and interfere with innate immunity.This review will focus on the induction of type I IFN response by HSV during acute infection and current knowledge of mechanisms by which HSV interferes with this induction process.     

The pros and cons of interferons for oncolytic virotherapy

Interferons (IFN) are potent immune stimulators that play key roles in both innate and adaptive immune responses. They are considered the first line of defense against viral pathogens and can even be used as treatments to boost the immune system. While viruses are usually seen as a threat to the host, an emerging class of cancer therapeutics exploits the natural capacity of some viruses to directly infect and kill cancer cells. The cancer-specificity of these bio-therapeutics, called oncolytic viruses (OVs), often relies on defective IFN responses that are frequently observed in cancer cells, therefore increasing their vulnerability to viruses compared to healthy cells. To ensure the safety of the therapy, many OVs have been engineered to further activate the IFN response. As a consequence of this IFN over-stimulation, the virus is cleared faster by the immune system, which limits direct oncolysis. Importantly, the therapeutic activity of OVs also relies on their capacity to trigger anti-tumor immunity and IFNs are key players in this aspect. Here, we review the complex cancer–virus–anti-tumor immunity interplay and discuss the diverse functions of IFNs for each of these processes.     

Innate immunity and adjuvants

Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection.     

Host responses from innate to adaptive immunity after vaccination: Molecular and cellular events

The availability of effective vaccines has had the most profound positive effect on improving the quality of public health by preventing infectious diseases. Despite many successful vaccines, there are still old and new emerging pathogens against which there is no vaccine available. A better understanding of how vaccines work for providing protection will help to improve current vaccines as well as to develop effective vaccines against pathogens for which we do not have a proper means to control. Recent studies have focused on innate immunity as the first line of host defense and its role in inducing adaptive immunity; such studies have been an intense area of research, which will reveal the immunological mechanisms how vaccines work for protection. Toll-like receptors (TLRs), a family of receptors for pathogen-associated molecular patterns on cells of the innate immune system, play a critical role in detecting and responding to microbial infections. Importantly, the innate immune system modulates the quantity and quality of longterm T and B cell memory and protective immune responses to pathogens. Limited studies suggest that vaccines which mimic natural infection and/or the structure of pathogens seem to be effective in inducing long-term protective immunity. A better understanding of the similarities and differences of the molecular and cellular events in host responses to vaccination and pathogen infection would enable the rationale for design of novel preventive measures against many challenging pathogens.     

Identification of lncRNA‐155 encoded by MIR155HG as a novel regulator of innate immunity against influenza A virus infection

Long noncoding RNAs (lncRNAs) are single‐stranded RNA molecules longer than 200 nt that regulate many cellular processes. MicroRNA 155 host gene (MIR155HG) encodes the microRNA (miR)‐155 that regulates various signalling pathways of innate and adaptive immune responses against viral infections. MIR155HG also encodes a lncRNA that we call lncRNA‐155. Here, we observed that expression of lncRNA‐155 was markedly upregulated during influenza A virus (IAV) infection both in vitro (several cell lines) and in vivo (mouse model). Interestingly, robust expression of lncRNA‐155 was also induced by infections with several other viruses. Disruption of lncRNA‐155 expression in A549 cells diminished the antiviral innate immunity against IAV. Furthermore, knockout of lncRNA‐155 in mice significantly increased IAV replication and virulence in the animals. In contrast, overexpression of lncRNA‐155 in human cells suppressed IAV replication, suggesting that lncRNA‐155 is involved in host antiviral innate immunity induced by IAV infection. Moreover, we found that lncRNA‐155 had a profound effect on expression of protein tyrosine phosphatase 1B (PTP1B) during the infection with IAV. Inhibition of PTP1B by lncRNA‐155 resulted in higher production of interferon‐beta (IFN‐β) and several critical interferon‐stimulated genes (ISGs). Together, these observations reveal that MIR155HG derived lncRNA‐155 can be induced by IAV, which modulates host innate immunity during the virus infection via regulation of PTP1B‐mediated interferon response.