微生物学报

结核分枝杆菌诱导IFN-β产生在免疫调控中的作用

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黄蓓 , 孟祥苗 , 田江瑶 , 宋厚辉 ^* , 杨杨 ^*

微生物学报 | 综述 2024,64(2): 331-343

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微生物学报 | 综述 2024, 64(2): 331-343

结核分枝杆菌诱导IFN-β产生在免疫调控中的作用

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黄蓓, 孟祥苗, 田江瑶, 宋厚辉^*, 杨杨^*

作者信息

浙江农林大学动物科技学院·动物医学院动物健康互联网检测技术浙江省工程研究中心浙江省动物医学与健康管理国际科技合作基地浙江省畜禽绿色生态健康养殖应用技术研究重点实验室中澳动物健康大数据分析联合实验室, 浙江杭州 311300

Research progress in the role of IFN-β production induced byMycobacterium tuberculosis in immune regulation

Bei HUANG, Xiangmiao MENG, Jiangyao TIAN, Houhui SONG^*, Yang YANG^*

Affiliations

China-Australia Joint Laboratory for Animal Health Big Data Analytics, Key Laboratory of Applied Technology on Green-eco-healthy Animal Husbandry of Zhejiang Province, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, Zhejiang Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Hangzhou 311300, Zhejiang, China

出版时间: 2024-02-04 doi: 10.13343/j.cnki.wsxb.20230416

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摘要

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结核分枝杆菌是导致结核病的病原体，也是影响全球数百万人健康的病原体之一。机体中多种模式识别受体(pattern recognition receptor, PRR)可识别入侵的结核分枝杆菌，如DNA和RNA传感器，从而激活天然免疫系统并诱导干扰素-β (interferon-β, IFN-β)产生。虽然IFN-β是先天抗病毒应答的主要效应因子，但其在结核分枝杆菌感染中的作用仍具有争议。结核分枝杆菌感染诱导的IFN-β产生可以促进细菌生长，并增强细菌在宿主中的存活率，但用IFN-β处理细胞后再感染结核分枝杆菌，则可增强抗菌作用，保护宿主。因此，本综述将重点关注可识别结核分枝杆菌并诱导的IFN-β产生的PRR及其下游信号通路，并着重探讨IFN-β在介导结核分枝杆菌调控免疫功能中的作用，尤其是IFN-β与IL-1β之间的相互抑制性调节，旨在为进一步揭示结核分枝杆菌致病机制及结核病治疗药物研发提供新思路。

关键词

结核分枝杆菌 / 干扰素β / 信号通路

Abstract

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Mycobacterium tuberculosis (Mtb), the pathogen of tuberculosis (TB), threatens the health of millions of people worldwide. The pattern recognition receptors (PRRs) including DNA and RNA sensors on immune cells recognize the invaded Mtb to activate the innate immune system and induce the production of interferon-beta (IFN-β). IFN-β is a major effector cytokine in innate antiviral response, while its role in the host response to Mtb infection remains controversial. IFN-β induced by Mtb can promote bacterial growth and improve the bacterial survival in the host. However, IFN-β treatment before Mtb infection can protect the host from bacterial infection. Focusing on the PRR signaling pathways that can recognize Mtb and mediate the IFN-β production, this review expounds the role of IFN-β in mediating the regulation of immune function by Mtb, especially the mutual inhibitory effect between IFN-β and IL-1β, aiming to reveal the pathogenic mechanism of Mtb and facilitate future research and development of anti-TB drugs.

Key words

Mycobacterium tuberculosis / IFN-β / signaling pathway

引用本文

黄蓓, 孟祥苗, 田江瑶, 宋厚辉, 杨杨. 结核分枝杆菌诱导IFN-β产生在免疫调控中的作用. 微生物学报, 2024 , 64 (2) : 331 -343 . DOI: 10.13343/j.cnki.wsxb.20230416

Bei HUANG, Xiangmiao MENG, Jiangyao TIAN, Houhui SONG, Yang YANG. Research progress in the role of IFN-β production induced byMycobacterium tuberculosis in immune regulation[J]. Acta Microbiologica Sinica, 2024 , 64 (2) : 331 -343 . DOI: 10.13343/j.cnki.wsxb.20230416

正文

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结核病是一种高度传染性疾病，据估计，全球约有四分之一的人口感染了结核病，如果不进行治疗，死亡率可达50%^[1-2]。根据世卫组织《2022年全球结核病报告》，2021年全球新增结核病患者约有1 060万人，而因结核病死亡的人数约有160万，因此，结核病也是引发全球公共健康问题的主要威胁之一^[3-4]。结核分枝杆菌(Mycobacterium tuberculosis, Mtb)是引起结核病的主要病原体，作为一种典型的细胞内病原体，其在感染过程中可被宿主免疫细胞表面的模式识别受体(pattern recognition receptor, PRR)或细胞内的核酸感受器识别。通常PRR识别入侵病原体成分后，会触发宿主的免疫防御机制，经过一系列信号途径激活宿主的天然免疫反应，如TLRs/MyD88/TIRF、cGAS/STING、RIG-1/MAVS等信号途径^[5]。这些途径最终通过转录因子、干扰素调节因子(interferon regulatory factor, IRF)和核因子κB (nuclear factor kappa-B, NF-κB)的激活，导致Ⅰ型干扰素(interferon, IFNs)基因表达以及其他促炎因子产生。IFN-β是Ⅰ型IFNs中的一员，在大多数病毒感染中具有保护作用，但在结核分枝杆菌等细菌感染中的作用仍有争议。多数学者认为在细菌感染宿主的过程中IFN-β反而有利于细菌的感染^[6]，且与结核病的病程密切相关^[7-8]。研究发现IFNAR1突变导致的Ⅰ型IFN信号减少可降低人类感染结核病的风险^[9]，这说明结核分枝杆菌很有可能通过调控IFN-β信号通路来达到免疫逃逸的作用。因此，IFN-β参与Mtb的免疫逃避机制也是近年来研究的一个重要领域，深入了解结核分枝杆菌通过哪些信号途径诱导IFN-β产生及IFN-β在细菌感染中的双重作用，有助于结核病的防控和治疗，为结核病治疗药物开发提供新思路。

1 结核分枝杆菌诱导IFN-β信号通路的途径

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1.1 cGAS/cGAMP/STING途径

环磷酸腺苷-鸟苷酸合成酶(cyclic guanosine monophosphate-adenosine monophosphate synthase, cGAS)是细胞质中的DNA感受器，可以识别来自病毒、细菌、线粒体、微核和逆转录元素的双链DNA (double strand DNA, dsDNA)。cGAS识别到dsDNA后，可以催化环磷酸腺苷-鸟苷酸(cyclic guanosine monophosphate-adenosine monophosphate, cGAMP)的产生^[10]，而cGAMP与干扰素基因刺激因子(stimulator of interferon genes, STING)结合后诱导STING发生构象改变，进而激活下游的IRF3^[11]和NF-κB^[12]，诱导Ⅰ型干扰素和炎症因子的产生^[11-14]。前期研究结果也显示，cGAS识别入侵病原体后，可促进cGAMP释放，并诱导STING二聚化和核转移，从而导致IFN-β产生^[15]。在宿主细胞感染期间，结核分枝杆菌等凭借ESAT-6分泌系统-1 (ESAT-6 secretion system 1, ESX-1)能够从吞噬溶酶体中转移到细胞质中，这一过程为宿主细胞质受体感知分枝杆菌菌体DNA提供了潜在的机会^[16-17]。2015年，Collins等、Watson等和Ablasser等也先后证实cGAS可以识别结核分枝杆菌DNA，进而诱导STING/TBK1信号通路的激活，这一过程需要结核分枝杆菌ESX-1分泌系统破坏吞噬小体^[18-20]。无论是在人单核细胞THP-1还是小鼠巨噬细胞BMDMs中，cGAS和STING基因敲除均可造成结核分枝杆菌诱导的IFN-β显著性降低。STING也可以作为主要的模式识别受体，识别细菌环二核苷酸(cyclic dinucleotides, CDNs)直接激活STING^[21-23]，如单增李斯特菌^[24-25]和化脓链球菌^[26]。与这2种细菌相似，结核分枝杆菌基因组编码的一种二腺核苷酸环化酶(disA或dacA, Rv3586, MT3692)，可将ATP或ADP转化成c-di-AMP^[22]，从而通过STING-IRF途径诱导IFN-β产生^[23]，同时，敲除Rv3586可以使IFN-β表达降低80%，但敲除编码环二腺苷酸磷酸二酯酶基因cnpB则使IFN-β升高10倍^[27]。这一结果与先前的发现相反，2012年Manzanillo等发现敲除Rv3586编码二腺苷酸环化酶基因并不影响结核分枝杆菌诱导的IFN-β的产生^[28]，因此，c-di-AMP对调控IFN-β的调控作用仍具有争议。此外，结核分枝杆菌还可以促进线粒体DNA的释放来激活cGAS信号通路。Wiens等^[29]研究发现结核分枝杆菌复合群中的不同菌株诱导IFN-β的能力不同，这种差异与细菌DNA无关，而与线粒体DNA的释放有关。MitoQ是线粒体特异性抗氧化剂，它可以抑制结核分枝杆菌诱发的线粒体DNA的释放以及IFN-β的生成^[29]。然而，体内研究表明，虽然结核分枝杆菌感染时，可通过cGAS和STING诱导IFN-β表达上升，但是在缺失cGAS或STING后，小鼠感染结核分枝杆菌后1−3个月的临床结果与野生型小鼠相似，其存活率、体重、细菌载量以及肺部炎症都没有显著变化，表明cGAS-STING途径并不是体内抵抗结核分枝杆菌感染的必要条件^[30]。这一结果与Collins等所示的cGAS缺失小鼠相较于STING^gt/gt和野生型(wild type, WT)小鼠更容易感染结核分枝杆菌且更早出现小鼠死亡不同^[18]，这可能是由于2组实验所用毒株和感染剂量的不同造成生存曲线差异。

1.2 RIG-1/MAVS途径

RIG-I-MAVS信号通路是一种抗病毒感染的天然免疫保护系统，视黄醇诱导型基因(retinoic acid-inducible gene I, RIG-1)和黑色素瘤分化相关蛋白5 (melanoma differentiation associated gene 5, MDA5)识别dsRNA被激活后其构象会发生改变，随后与线粒体抗病毒信号蛋白(mitochondrial antiviral-signalling protein, MAVS)中的CARD结构域相互作用，MAVS随后激活TBK1和κb激酶-ε (IκB kinase ε, IKKε)，从而激活IRF3和IRF7，并与NF-κB一起诱导Ⅰ型干扰素和其他抗病毒蛋白表达^[31]。前期研究发现PCV2可通过RIG-1/MDA5-MAVS-IRF3途径诱导IFN-β产生^[32]。除了能够识别病毒，RIG-1和MDA5被证明可识别多种细菌RNA，如单增李斯特菌^[33]、嗜肺军团菌^[34-35]和幽门螺杆菌^[36]等。2017年，Andreu等通过结核分枝杆菌感染巨噬细胞后的差异基因通路分析发现，结核分枝杆菌感染可诱导RIG-1和MDA5表达上升，并导致其下游效应因子IFN-β及多种干扰素刺激基因(interferon-stimulated genes, ISGs)的表达上升^[37]。随后，Cheng等^[38]发现结核分枝杆菌可以通过SecA2释放自身RNA到宿主细胞质中，但这一过程需要细菌先通过ESX-1分泌系统从吞噬小体进入细胞质中。释放到细胞质中的结核分枝杆菌polA和ppe11等RNA可与RIG-1结合，但并不与MDA5结合，进而激活下游的MAVS/IRF7信号通路，诱导IFN-β产生，另外，与野生型小鼠相比，MAVS^−/−小鼠感染结核分枝杆菌后的存活时间显著延长，其肺脏和脾脏中的载菌量显著减少，血清中的IFN-β也显著减少，这进一步说明RNA传感器在分枝杆菌感染宿主中发挥着重要作用^[38]。然而，值得注意的是，结核分枝杆菌的RNA仅能在感染巨噬细胞8 h和24 h后检测到，在感染4 h后并不能检测到；同样地，siRNA敲低RIG-1和/或MAVS并不影响感染4 h后的IFN-β产生，但敲低STING则会导致IFN-β mRNA在感染后4、8、24 h均显著下降，这说明结核分枝杆菌在感染最早期还是主要通过DNA感受器而非RNA感受器来诱导IFN-β产生^[38]。由于以上结果并没有揭示MDA5在结核分枝杆菌感染宿主细胞时对IFN-β产生的影响，以及RNA传感器在感染初期对宿主细胞中细菌复制的影响，Ranjbar等针对上述问题进行研究。结果发现，结核分枝杆菌感染人原代单核细胞来源巨噬细胞(monocyte-derived macrophages, MDM)和传代细胞THP-1后，RIG-1和MDA5的mRNA水平及IFN-β表达均显著上升，结核分枝杆菌感染RIG-1-、MDA5-或MAVS-缺失THP-1细胞4 h后，细菌细胞内的存活显著增加，表明RNA传感器在感染初期可抑制结核分枝杆菌的生长^[39]。

1.3 其他途径

髓系细胞触发受体2 (triggering receptor expressed on myeloid cells 2, TREM2)是一种介导抗炎免疫信号的跨膜表面受体，可识别细菌的成分、DNA、脂蛋白和磷脂^[40-41]。Dabla等发现结核分枝杆菌可与巨噬细胞中的TREM2结合，导致STING依赖性的TREM2表达上调，从而促进IL-10和IFN-β的产生，而IFN-β水平的升高可抑制活性氧(reactive oxygen species, ROS)和促炎因子的产生，并抑制巨噬细胞死亡，从而导致结核分枝杆菌在细胞内的存活率上升；同时，敲除TREM2的THP-1细胞中IFN-β水平显著下降，结核分枝杆菌的复制和存活率显著下降，而过表达TREM2的THP-1细胞中IFN-β水平显著上升，且结核分枝杆菌的复制和存活率也显著上升^[42]。

胞质中的核苷酸结合寡聚结构域(nucleotide-binding oligomerization domain, NOD)蛋白也是一种重要模式识别受体，其家族中的NOD2是抗细菌免疫的关键模式识别受体，可通过识别细菌胞壁成分分子胞壁酰二肽(muramyl dipeptide, MDP)介导免疫应答信号途径活化，从而在先天免疫系统中发挥重要作用^[43]。2009年，Pandey等发现结核分枝杆菌的MDP可以被NOD2/Rip2识别，激活TBK1/IRF5信号通路诱导IFN-β产生^[44]。另一种跨膜蛋白Toll样受体(Toll-like receptor, TLR)也可以识别结核分枝杆菌成分，TLR4可识别革兰氏阴性菌中的脂多糖，在结核分枝杆菌感染巨噬细胞时也可以被TLR4识别，不仅可通过MyD88途径介导的信号传导并诱导Ⅰ型IFN的产生，也可以通过激活TRIF诱导IRF3表达从而诱导IFN-β产生^[28,45]。据报道，C型凝集素受体(C-type lectin receptors, CLRs)也可识别结核分枝杆菌，并诱导B细胞产生Ⅰ型IFN和增强DCs中的Ⅰ型IFN反应^[46-47]。

双链RNA依赖的蛋白激酶(RNA-dependent kinase, PKR)途径是独立于RIG-1/MAVS途径可识别dsRNA的一种RNA传感器，与dsRNA结合后被激活，激活的PKR通过磷酸化Ser51导致蛋白质合成不能完成，从而直接或间接激活激酶途径，如丝裂原活化蛋白激酶(mitosolysis activates protein kinase, MAPK)途径，并导致IFN-β上升^[48-49]。研究表明，结核分枝杆菌感染THP-1细胞后会导致PKR mRNA和蛋白水平升高，从而诱导eIF2a磷酸化和IFN-β产生，而PKR缺失则导致细胞内结核分枝杆菌生长显著增强，该结果与RIG-1/MAVS的结果一致^[39]。

综上所述，结核分枝杆菌感染时可被宿主中的多种PRRs识别，并通过DNA和RNA等多条信号途径诱导IFN-β产生(图1)，但目前并没有文献系统报道这些信号通路间是否存在交互作用，仅有Cheng等提出结核分枝杆菌在感染前期是通过DNA途径中cGAS/STING信号通路诱导IFN-β产生，后期是通过RNA途径中的RIG-1/MAVS/IRF7信号通路诱导IFN-β产生^[38]，但其他诱导IFN-β产生的信号通路之间是否存在相互作用以及结核分枝杆菌中的哪些成分参与调控IFN-β产生还不清楚，因此，结核分枝杆菌感染时的诱导免疫应答的具体成分及诱导IFN-β产生途径还需深入探究。

2 IFN-β在结核分枝杆菌感染中的作用

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2.1 IFN-β在结核分枝杆菌感染中的调节作用

IFN-β是一种多效性细胞因子，可在多种病原体感染时产生，如病毒、细菌和原生动物等，在刺激先天和适应性免疫反应中起着至关重要的作用。IFN-β的抗病毒和免疫调节作用在病毒感染中已经得到充分研究，但是其在细菌感染中的免疫作用仍然具有争议。单增李斯特菌感染时可诱导细胞释放IFN-β并激活ISG，产生抗菌作用，但是有研究表明小鼠体内产生IFN-β的量与抗菌能力成反比，产生的IFN-β可促进李斯特杆菌感染，且在IFN-β缺失小鼠体内可产生更多的IFN-γ，从而增强抗菌作用^[50]；Bouchonnet等的研究结果也表明，牛分枝杆菌在IFN-β预处理的巨噬细胞中可以提高细菌自身的存活率，这也进一步表明IFN-β具有促菌作用^[51]。前面已经表明结核分枝杆菌感染可以通过胞质DNA和RNA途径诱导IFN-β产生，与其他细菌相似，结核分枝杆菌也被证明可利用宿主产生的IFN-β来增强其在宿主中的存活能力^[52]。感染小鼠和人巨噬细胞实验结果表明，只有毒力强的分枝杆菌才能诱导Ⅰ型IFN产生，因此IFN-β的产生可能与分枝杆菌毒力以及增强宿主易感性有关^[29]。虽然IFN-β是否加重结核病的确切机制尚不完全清楚，但缺失IFNAR1或抑制Ⅰ型IFN产生时有利于小鼠抵抗结核分枝杆菌感染^[53]；Zhang等的研究结果也表明，IFNAR1突变导致的Ⅰ型IFN信号减少可降低人类感染结核病的风险^[9]；另外，结核分枝杆菌的分泌蛋白Rv3722c可与肿瘤坏死因子受体作用因子3 (tumor necrosis factor receptor-associated factor 3, TRAF3)相互作用阻断MAPK和NF-κB通路，导致IFN-β表达显著增加，以及IL-1β、IL-6、IL-12p40和TNF-a表达显著降低，并促进结核分枝杆菌在巨噬细胞中的存活率；同时，敲除TRAF3后细胞内结核分枝杆菌的存活率降低，进一步表明IFN-β对结核分枝杆菌在细胞内的生存具有促进作用^[54]。然而，在分枝杆菌载量相对较低的情况下，信号传导率或Ⅰ型IFN水平的降低可能引发宿主保护反应，从而保护患者免受细菌的侵害^[52]，有研究表明，结核分枝杆菌感染小鼠BMDM细胞后用IFN-β处理，可诱导一氧化氮合酶2 (nitric oxide synthase 2, Nos2)和NO表达显著上升，从而增强宿主对结核分枝杆菌的抵抗力，降低胞内菌的存活率^[55]；在卡介苗中重组表达ESX-1可增强疫苗接种对结核分枝杆菌感染的保护作用，且这种增强的保护作用与诱导的IFN-β增加有关^[56]；Madhvi等的研究结果也表明，IFN-β处理结核分枝杆菌感染的THP-1细胞可上调干扰素诱导的四肽重复蛋白(interferon-induced proteins with tetracopeptides, IFITs)的表达，而IFITs的高表达可降低耐药分枝杆菌的体外存活，对宿主具有免疫保护作用^[57]。目前关于IFN-β在结核分枝杆菌感染中的机制仍具有争议，其在结核病中的具体作用机制还需要更多的研究证明。

2.2 IFN-β与IL-1β在结核分枝杆菌感染中的相互拮抗作用

前期研究结果显示，牛分枝杆菌感染巨噬细胞可激活NLRP3和AIM2炎症小体，并诱导caspase-1剪切和IL-1β分泌^[58-59]，同样，结核分枝杆菌感染除了可诱导IFN-β产生以外，也可以激活NLRP3和AIM2炎性小体，并引起IL-1β和IL-18分泌^[60]。IL-1β被证明是先天免疫中抵抗结核分枝杆菌感染的主要细胞因子，可调控结核分枝杆菌的活性，并增强巨噬细胞的抗菌功能^[61]。体外研究表明，结核分枝杆菌感染巨噬细胞是以NLRP3炎症小体依赖的方式诱导IL-1β分泌，而体内研究表明IL-1β的产生是独立于NLRP3炎症小体的；另外，AIM2缺陷小鼠的研究结果也表明，缺失AIM2小鼠更容易受结核分枝杆菌感染，并伴随IL-1β、IL-18的下调和Th1免疫反应受损^[62]。研究结果发现，IFN-β可抑制NLRP3依赖途径的IL-1β产生，一方面Ⅰ型IFN信号通过STAT1转录因子抑制NLRP1和NLRP3炎症小体的活性，从而抑制caspase-1依赖性IL-1β的成熟；另一方面Ⅰ型IFN通过STAT1依赖方式诱导IL-10分泌，自分泌的IL-10通过STAT3降低pro-IL-1β的产量，从而抑制IL-1β表达^[63]；这种IL-1β分泌减少与结核分枝杆菌感染宿主的易感性增加相关^[64]。此外，在分枝杆菌感染过程中，IFN-β信号的缺失可导致IL-1β升高，同时IFN-β受体缺失小鼠分别感染多种分枝杆菌菌株时，小鼠中细菌载量均显著降低^[65]；Dorhoi等也发现，缺乏IFNAR1的小鼠在感染结核分枝杆菌后死亡率降低^[66]；而当添加外源性IFN-β时，结核分枝杆菌^[53]或牛分枝杆菌^[59]感染BMDM产生的IL-1β显著减少，结核分枝杆菌感染的小鼠则表现出肺部病理情况加重以及细菌载菌量上升^[65]。以上结果均表明IFN-β可抑制IL-1β表达，同时也揭示了IFN-β的免疫抑制和促细菌生长作用。

相反，IL-1β也可通过多种途径抑制IFN-β产生，Yan等发现结核分枝杆菌感染时，AIM2-IL-1β途径中的ASC可与STING相互作用阻断TBK1与STING的结合，从而负调控STING-IFN-β途径，抑制IFN-β产生^[67]，siRNA敲低AIM2后，IFN-β表达量显著上升，也进一步说明AIM2激活对IFN-β产生具有负调控作用^[59]；IL-1β也可以通过增强类花生酸类脂质介质，如前列腺素E2 (prostaglandin E2, PGE2)的产生来抑制IFN-β的分泌和结核分枝杆菌复制^[53]。另外，在牛分枝杆菌感染期间，caspase-1可通过剪切cGAS抑制下游TBK1-IRF3信号传导，从而抑制IFN-β的产生，而caspase-1缺失则导致IFN-β表达上升^[68]；铜绿假单胞菌感染宿主诱导产生的IL-1β可通过cGAS-STING-TBK1途径抑制IFN-β产生，IL-1β通过激活AKT激酶降低cGAMP表达，从而抑制STING-TBK1-IRF3轴激活，并抑制IFN-β产生^[69]。IFN-β与IL-1β通路之间的相互作用在细菌感染过程中发挥重要作用(图2)，细菌利用IFN-β来逃避宿主对它的抗菌作用并促进自身复制，IL-1β介导的炎症反应有利于抗菌免疫反应，两者之间的拮抗作用能够使机体对细菌的反应不会过于强烈从而对自身造成伤害，且根据感染类型，诱导IFN-β和pro-IL-1β之间的平衡可以决定最终成熟IL-1β的水平，并在一定程度上维持机体的稳态。

3 总结与展望

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结核病是由结核分枝杆菌引起的一种慢性传染疾病，是全球第二大传染性疾病“杀手”，严重影响全球人类的健康^[70]。目前，临床上对结核病的治疗主要依赖于利福平、异烟肼等一、二线抗结核药，但多重耐药性的出现使得结核病的传播和治疗复杂化。IFN-β等Ⅰ型干扰素被证明参与结核分枝杆菌介导的免疫逃避机制，进一步聚焦结核分枝杆菌诱导IFN-β信号通路激活的机制以及该通路在细菌感染中发挥的作用机制，不仅可以为研究结核分枝杆菌免疫逃逸机制提供理论基础，也为预防和治疗结核病提供新的策略。此外，结核分枝杆菌在感染过程中不仅激活炎性小体从而调控IL-1β的分泌，也可通过模式识别受体诱导IFN-β产生，而IL-1β和IFN-β在宿主抵抗结核杆菌感染分别起到保护和非保护作用，并且两者之间存在拮抗，而这种拮抗作用可能决定了病程的走向^[71]。目前的研究往往多关注于结核分枝杆菌菌体自身的毒力因子或者其诱导的宿主单一信号通路，而很少关注于不同信号通路之间的互作对病程的影响。因此，深入了解宿主针对结核杆菌感染的保护性免疫反应和非保护性免疫反应，深入探索2种免疫反应间的相互拮抗机制，对于开发新型结核病防治措施至关重要。

基金

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浙江省自然科学基金(LTGD23C180001)
浙江农林大学学校科研发展基金(2022LFR067)
浙江省属高校基本科研业务费专项基金(2020YQ008)
国家自然科学基金(32272951)

参考文献

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文献

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参考文献引证文献

排序方式：

[1]

HOUBEN RMGJ, DODD PJ.The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling[J].PLoS Medicine,2016,13(10):e1002152.

https://doi.org/10.1371/journal.pmed.1002152

[2]

TIEMERSMA EW, van der WERF MJ, BORGDORFF MW, WILLIAMS BG, NAGELKERKE NJD.Natural history of tuberculosis: duration and fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review[J].PLoS One,2011,6(4):e17601.

https://doi.org/10.1371/journal.pone.0017601

[3]

BAGCCHI S.WHO's global tuberculosis report 2022[J].The Lancet Microbe,2023,4(1):e20.

https://doi.org/10.1016/S2666-5247(22)00359-7

[4]

World Health Organization. Global tuberculosis report 2022[EB/OL]. World Health Organization, 2022.

[5]

SNYDER DT, HEDGES JF, JUTILA MA.Getting inside type Ⅰ IFNs: type Ⅰ IFNs in intracellular bacterial infections[J].Journal of Immunology Research,2017,2017:9361802.

[6]

TRAVAR M, PETKOVIC M, VERHAZ A.Type Ⅰ, Ⅱ, and Ⅲ interferons: regulating immunity toMycobacterium tuberculosis infection[J].Archivum Immunologiae et Therapiae Experimentalis,2016,64(1):19-31.

https://doi.org/10.1007/s00005-015-0365-7

[7]

MALIREDDI RKS, KANNEGANTI TD.Role of type Ⅰ interferons in inflammasome activation, cell death, and disease during microbial infection[J].Frontiers in Cellular and Infection Microbiology,2013,3:77.

[8]

MANCA C, TSENOVA L, BERGTOLD A, FREEMAN S, TOVEY M, MUSSER JM, BARRY CE 3rd, FREEDMAN VH, KAPLAN G.Virulence of aMycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-alpha/beta[J].Proceedings of the National Academy of Sciences of the United States of America,2001,98(10):5752-5757.

[9]

ZHANG GL, DEWEERD NA, STIFTER SA, LIU L, ZHOU BP, WANG WF, ZHOU YP, YING BW, HU XJ, MATTHEWS AY, ELLIS M, TRICCAS JA, HERTZOG PJ, BRITTON WJ, CHEN XC, FENG CG.A proline deletion in IFNAR1 impairs IFN-signaling and underlies increased resistance to tuberculosis in humans[J].Nature Communications,2018,9(1):85.

https://doi.org/10.1038/s41467-017-02611-z

[10]

WU JX, SUN LJ, CHEN X, DU FH, SHI HP, CHEN C, CHEN ZJ.Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA[J].Science,2013,339(6121):826-830.

https://doi.org/10.1126/science.1229963

[11]

LIU SQ, CAI X, WU JX, CONG Q, CHEN X, LI T, DU FH, REN JY, WU YT, GRISHIN NV, CHEN ZJ.Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation[J].Science,2015,347(6227):aaa2630.

https://doi.org/10.1126/science.aaa2630

[12]

ABE T, BARBER GN.Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-κB activation through TBK1[J].Journal of Virology,2014,88(10):5328-5341.

https://doi.org/10.1128/JVI.00037-14

[13]

CAI X, CHIU YH, CHEN ZJ.The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling[J].Molecular Cell,2014,54(2):289-296.

https://doi.org/10.1016/j.molcel.2014.03.040

[14]

胡燕萍, 许锦霞, 徐阿慧, 程昌勇, 宋厚辉, 杨杨.宿主cGAS-STING信号通路调控机制的研究进展[J].中国预防兽医学报,2022,44(12):1344-1351.

HU YP, XU JX, XU AH, CHENG CY, SONG HH, YANG Y.Recent advances in the regulation mechanism of host cGAS-STING signaling pathway[J].Chinese Journal of Preventive Veterinary Medicine,2022,44(12):1344-1351 (in Chinese).

[15]

HUANG B, ZHANG LL, LU MQ, LI JS, LV YJ.PCV₂ infection activates the cGAS/STING signaling pathway to promote IFN-β production and viral replication in PK-15 cells[J].Veterinary Microbiology,2018,227:34-40.

https://doi.org/10.1016/j.vetmic.2018.10.027

[16]

van der WEL N, HAVA D, HOUBEN D, FLUITSMA D, van ZON M, PIERSON J, BRENNER M, PETERS PJ.M.tuberculosis andM.leprae translocate from the phagolysosome to the cytosol in myeloid cells[J].Cell,2007,129(7):1287-1298.

https://doi.org/10.1016/j.cell.2007.05.059

[17]

HOUBEN D, DEMANGEL C, van INGEN J, PEREZ J, BALDEÓN L, ABDALLAH AM, CALEECHURN L, BOTTAI D, van ZON M, de PUNDER K, van der LAAN T, KANT A, BOSSERS-de VRIES R, WILLEMSEN P, BITTER W, van SOOLINGEN D, BROSCH R, van der WEL N, PETERS PJ.ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria[J].Cellular Microbiology,2012,14(8):1287-1298.

https://doi.org/10.1111/j.1462-5822.2012.01799.x

[18]

COLLINS AC, CAI HC, LI T, FRANCO LH, LI XD, NAIR VR, SCHARN CR, STAMM CE, LEVINE B, CHEN ZJ, SHILOH MU.Cyclic GMP-AMP synthase is an innate immune DNA sensor forMycobacterium tuberculosis[J].Cell Host & Microbe,2015,17(6):820-828.

[19]

WATSON RO, BELL SL, MacDUFF DA, KIMMEY JM, DINER EJ, OLIVAS J, VANCE RE, STALLINGS CL, VIRGIN HW, COX JS.The cytosolic sensor cGAS detectsMycobacterium tuberculosis DNA to induce type Ⅰ interferons and activate autophagy[J].Cell Host & Microbe,2015,17(6):811-819.

[20]

ABLASSER A, DORHOI A.Inflammasome activation and function during infection withMycobacterium tuberculosis//Current Topics in Microbiology and Immunology[J].Cham: Springer International Publishing,2016:183-197.

[21]

BURDETTE DL, MONROE KM, SOTELO-TROHA K, IWIG JS, ECKERT B, HYODO M, HAYAKAWA Y, VANCE RE.STING is a direct innate immune sensor of cyclic di-GMP[J].Nature,2011,478(7370):515-518.

https://doi.org/10.1038/nature10429

[22]

BAI YL, YANG J, ZHOU X, DING XX, EISELE LE, BAI GC.Mycobacterium tuberculosis Rv3586 (DacA) is a diadenylate cyclase that converts ATP or ADP into c-di-AMP[J].PLoS One,2012,7(4):e35206.

https://doi.org/10.1371/journal.pone.0035206

[23]

DEY B, DEY RJ, CHEUNG LS, POKKALI S, GUO HD, LEE JH, BISHAI WR.A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis[J].Nature Medicine,2015,21(4):401-406.

https://doi.org/10.1038/nm.3813

[24]

WOODWARD JJ, IAVARONE AT, PORTNOY DA.C-di-AMP secreted by intracellularListeria monocytogenes activates a host type Ⅰ interferon response[J].Science,2010,328(5986):1703-1705.

https://doi.org/10.1126/science.1189801

[25]

LOUIE A, BHANDULA V, PORTNOY DA.Secretion of c-di-AMP byListeria monocytogenes leads to a STING-dependent antibacterial response during enterocolitis[J].Infection and Immunity,2020,88(12):e00407-20.

[26]

FAHMI T, FAOZIA S, PORT GC, CHO KH.The second messenger c-di-AMP regulates diverse cellular pathways involved in stress response, biofilm formation, cell wall homeostasis, SpeB expression, and virulence inStreptococcus pyogenes[J].Infection and Immunity,2019,87(6):e00147-19.

[27]

YANG J, BAI YL, ZHANG Y, GABRIELLE VD, JIN L, BAI GC.Deletion of the cyclic di-AMP phosphodiesterase gene (cnpB) inMycobacterium tuberculosis leads to reduced virulence in a mouse model of infection[J].Molecular Microbiology,2014,93(1):65-79.

https://doi.org/10.1111/mmi.12641

[28]

MANZANILLO PS, SHILOH MU, PORTNOY DA, COX JS.Mycobacterium tuberculosis activates the DNA-dependent cytosolic surveillance pathway within macrophages[J].Cell Host & Microbe,2012,11(5):469-480.

[29]

WIENS KE, ERNST JD.The mechanism for type Ⅰ interferon induction byMycobacterium tuberculosis is bacterial strain-dependent[J].PLoS Pathogens,2016,12(8):e1005809.

https://doi.org/10.1371/journal.ppat.1005809

[30]

MARINHO FV, BENMERZOUG S, ROSE S, CAMPOS PC, MARQUES JT, BÁFICA A, BARBER G, RYFFEL B, OLIVEIRA SC, QUESNIAUX VFJ.The cGAS/STING pathway is important for dendritic cell activation but is not essential to induce protective immunity againstMycobacterium tuberculosis infection[J].Journal of Innate Immunity,2018,10(3):239-252.

https://doi.org/10.1159/000488952

[31]

REHWINKEL J, GACK MU.RIG-I-like receptors: their regulation and roles in RNA sensing[J].Nature Reviews Immunology,2020,20(9):537-551.

https://doi.org/10.1038/s41577-020-0288-3

[32]

HUANG B, LI JS, ZHANG XC, ZHAO QL, LU MQ, LV YJ.RIG-1 and MDA-5 signaling pathways contribute to IFN-β production and viral replication in porcine circovirus virus type 2-infected PK-15 cellsin vitro[J].Veterinary Microbiology,2017,211:36-42.

https://doi.org/10.1016/j.vetmic.2017.09.022

[33]

ABDULLAH Z, SCHLEE M, ROTH S, ABU MRAHEIL M, BARCHET W, BÖTTCHER J, HAIN T, GEIGER S, HAYAKAWA Y, FRITZ JH, CIVRIL F, HOPFNER KP, KURTS C, RULAND J, HARTMANN G, CHAKRABORTY T, KNOLLE PA.RIG-I detects infection with liveListeria by sensing secreted bacterial nucleic acids[J].The EMBO Journal,2012,31(21):4153-4164.

https://doi.org/10.1038/emboj.2012.274

[34]

LAGANA P, SORACI L, GAMBUZZA ME, MANCUSO G, DELIA SA.Innate immune surveillance in the central nervous system followingLegionella pneumophila infection[J].CNS & Neurological Disorders Drug Targets,2017,16(10):1080-1089.

[35]

PARK B, PARK G, KIM J, LIM SA, LEE KM.Innate immunity againstLegionella pneumophila during pulmonary infections in mice[J].Archives of Pharmacal Research,2017,40(2):131-145.

https://doi.org/10.1007/s12272-016-0859-9

[36]

CHEOK YY, TAN GMY, LEE CYQ, ABDULLAH S, LOOI CY, WONG WF.Innate immunity crosstalk withHelicobacter pylori: pattern recognition receptors and cellular responses[J].International Journal of Molecular Sciences,2022,23(14):7561.

https://doi.org/10.3390/ijms23147561

[37]

ANDREU N, PHELAN J, de SESSIONS PF, CLIFF JM, CLARK TG, HIBBERD ML.Primary macrophages and J774 cells respond differently to infection withMycobacterium tuberculosis[J].Scientific Reports,2017,7:42225.

https://doi.org/10.1038/srep42225

[38]

CHENG Y, SCHOREY JS.Mycobacterium tuberculosis-induced IFN-β production requires cytosolic DNA and RNA sensing pathways[J].Journal of Experimental Medicine,2018,215(11):2919-2935.

https://doi.org/10.1084/jem.20180508

[39]

RANJBAR S, HARIDAS V, NAMBU A, JASENOSKY LD, SADHUKHAN S, EBERT TS, HORNUNG V, CASSELL GH, FALVO JV, GOLDFELD AE.Cytoplasmic RNA sensor pathways and nitazoxanide broadly inhibit intracellularMycobacterium tuberculosis growth[J].iScience,2019,22:299-313.

https://doi.org/10.1016/j.isci.2019.11.001

[40]

KOBER DL, BRETT TJ.TREM2-ligand interactions in health and disease[J].Journal of Molecular Biology,2017,429(11):1607-1629.

https://doi.org/10.1016/j.jmb.2017.04.004

[41]

WANG Y, CAO C, ZHU YT, FAN HF, LIU QJ, LIU YT, CHEN K, WU YJ, LIANG SP, LI MY, LI LX, LIU X, ZHANG YQ, WU CL, LU G, WU MH.TREM2/β-catenin attenuates NLRP3 inflammasome-mediated macrophage pyroptosis to promote bacterial clearance of pyogenic bacteria[J].Cell Death & Disease,2022,13(9):771.

[42]

DABLA A, LIANG YC, RAJABALEE N, IRWIN C, MOONEN CGJ, WILLIS JV, BERTON S, SUN J.TREM2 promotes immune evasion byMycobacterium tuberculosis in human macrophages[J].mBio,2022,13(4):e0145622.

https://doi.org/10.1128/mbio.01456-22

[43]

LEBER JH, CRIMMINS GT, RAGHAVAN S, MEYER-MORSE NP, COX JS, PORTNOY DA.Distinct TLR- and NLR-mediated transcriptional responses to an intracellular pathogen[J].PLoS Pathogens,2008,4(1):e6.

https://doi.org/10.1371/journal.ppat.0040006

[44]

PANDEY AK, YANG YB, JIANG ZZ, FORTUNE SM, COULOMBE F, BEHR MA, FITZGERALD KA, SASSETTI CM, KELLIHER MA.NOD2, RIP2 and IRF5 play a critical role in the type Ⅰ interferon response toMycobacterium tuberculosis[J].PLoS Pathogens,2009,5(7):e1000500.

https://doi.org/10.1371/journal.ppat.1000500

[45]

STANLEY SA, JOHNDROW JE, MANZANILLO P, COX JS.The type Ⅰ IFN response to infection withMycobacterium tuberculosis requires ESX-1-mediated secretion and contributes to pathogenesis[J].Journal of Immunology (Baltimore, Md: 1950),2007,178(5):3143-3152.

https://doi.org/10.4049/jimmunol.178.5.3143

[46]

BÉNARD A, SAKWA I, SCHIERLOH P, COLOM A, MERCIER I, TAILLEUX L, JOUNEAU L, BOUDINOT P, Al-SAATI T, LANG R, REHWINKEL J, LOXTON AG, KAUFMANN SHE, ANTON-LEBERRE V, O'GARRA A, SASIAIN MDC, GICQUEL B, FILLATREAU S, NEYROLLES O, HUDRISIER D.B cells producing type Ⅰ IFN modulate macrophage polarization in tuberculosis[J].American Journal of Respiratory and Critical Care Medicine,2018,197(6):801-813.

https://doi.org/10.1164/rccm.201707-1475OC

[47]

TROEGELER A, MERCIER I, COUGOULE C, PIETRETTI D, COLOM A, DUVAL C, VU MANH TP, CAPILLA F, POINCLOUX R, PINGRIS K, NIGOU J, RADEMANN J, DALOD M, VERRECK FAW, Al SAATI T, LUGO-VILLARINO G, LEPENIES B, HUDRISIER D, NEYROLLES O.C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type Ⅰ interferon signaling in dendritic cells[J].Proceedings of the National Academy of Sciences of the United States of America,2017,114(4):E540-E549.

[48]

BOU-NADER C, GORDON JM, HENDERSON FE, ZHANG JW.The search for a PKR code-differential regulation of protein kinase R activity by diverse RNA and protein regulators[J].RNA,2019,25(5):539-556.

https://doi.org/10.1261/rna.070169.118

[49]

ZHANG LY, XIANG WP, WANG GL, YAN ZZ, ZHU ZW, GUO Z, SENGUPTA R, CHEN AF, LOUGHRAN PA, LU B, WANG QD, BILLIAR TR.Interferon β (IFN-β) production during the double-stranded RNA (dsRNA) response in hepatocytes involves coordinated and feedforward signaling through Toll-like receptor 3 (TLR3), RNA-dependent protein kinase (PKR), inducible nitric oxide synthase (iNOS), and src protein[J].Journal of Biological Chemistry,2016,291(29):15093-15107.

https://doi.org/10.1074/jbc.M116.717942

[50]

DUSSURGET O, BIERNE H, COSSART P.The bacterial pathogenListeria monocytogenes and the interferon family: type Ⅰ, type Ⅱ and type Ⅲ interferons[J].Frontiers in Cellular and Infection Microbiology,2014,4:50.

[51]

BOUCHONNET F, BOECHAT N, BONAY M, HANCE AJ.Alpha/beta interferon impairs the ability of human macrophages to control growth ofMycobacterium bovis BCG[J].Infection and Immunity,2002,70(6):3020-3025.

https://doi.org/10.1128/IAI.70.6.3020-3025.2002

[52]

SHANMUGANATHAN G, ORUJYAN D, NARINYAN W, POLADIAN N, DHAMA S, PARTHASARATHY A, HA A, TRAN D, VELPURI P, NGUYEN KH, VENKETARAMAN V.Role of interferons inMycobacterium tuberculosis infection[J].Clinics and Practice,2022,12(5):788-796.

https://doi.org/10.3390/clinpract12050082

[53]

MAYER-BARBER KD, ANDRADE BB, OLAND SD, AMARAL EP, BARBER DL, GONZALES J, DERRICK SC, SHI RR, KUMAR NP, WEI W, YUAN X, ZHANG GL, CAI Y, BABU S, CATALFAMO M, SALAZAR AM, VIA LE, BARRY Ⅲ CE, SHER A.Host-directed therapy of tuberculosis based on interleukin-1 and type Ⅰ interferon crosstalk[J].Nature,2014,511(7507):99-103.

https://doi.org/10.1038/nature13489

[54]

LEI YY, CAO XJ, XU WZ, YANG B, XU YY, ZHOU W, DONG S, WU QJ, RAHMAN K, TYAGI R, ZHAO SH, CHEN X, CAO G.Rv3722c promotesMycobacterium tuberculosis survival in macrophages by interacting with TRAF3[J].Frontiers in Cellular and Infection Microbiology,2021,11:627798.

https://doi.org/10.3389/fcimb.2021.627798

[55]

BANKS DA, AHLBRAND SE, HUGHITT VK, SHAH S, MAYER-BARBER KD, VOGEL SN, EL-SAYED NM, BRIKEN V.Mycobacterium tuberculosis inhibits autocrine type Ⅰ IFN signaling to increase intracellular survival[J].The Journal of Immunology,2019,202(8):2348-2359.

https://doi.org/10.4049/jimmunol.1801303

[56]

GRÖSCHEL MI, SAYES F, SHIN SJ, FRIGUI W, PAWLIK A, ORGEUR M, CANETTI R, HONORÉ N, SIMEONE R, van der WERF TS, BITTER W, CHO SN, MAJLESSI L, BROSCH R.Recombinant BCG expressing ESX-1 ofMycobacterium marinum combines low virulence with cytosolic immune signaling and improved TB protection[J].Cell Reports,2017,18(11):2752-2765.

https://doi.org/10.1016/j.celrep.2017.02.057

[57]

MADHVI A, MISHRA H, CHEGOU NN, BAKER B.Increased interferon-induced protein with tetracopeptides (IFITs) reduces mycobacterial growth[J].Frontiers in Cellular and Infection Microbiology,2022,12:828439.

https://doi.org/10.3389/fcimb.2022.828439

[58]

YANG Y, XU PP, HE P, SHI FS, TANG YR, GUAN CY, ZENG H, ZHOU YS, SONG QJ, ZHOU B, JIANG S, SHAO CY, SUN J, YANG YC, WANG XD, SONG HH.Mycobacterial PPE13 activates inflammasome by interacting with the NATCH and LRR domains of NLRP3[J].FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology,2020,34(9):12820-12833.

https://doi.org/10.1096/fj.202000200RR

[59]

YANG Y, ZHOU XM, KOUADIR M, SHI FS, DING TJ, LIU CF, LIU J, WANG M, YANG LF, YIN XM, ZHAO DM.The AIM2 inflammasome is involved in macrophage activation during infection with virulentMycobacterium bovis strain[J].The Journal of Infectious Diseases,2013,208(11):1849-1858.

https://doi.org/10.1093/infdis/jit347

[60]

de ANDRADE FIGUEIRA MB, de LIMA DS, BOECHAT AL, DO NASCIMENTO FILHO MG, ANTUNES IA, da SILVA MATSUDA J, de ALBUQUERQUE RIBEIRO TR, FELIX LS, GONÇALVES ASF, da COSTA AG, RAMASAWMY R, PONTILLO A, OGUSKU MM, SADAHIRO A.Single-nucleotide variants in the AIM2-absent in melanoma 2 gene (rs1103577) associated with protection for tuberculosis[J].Frontiers in Immunology,2021,12:604975.

https://doi.org/10.3389/fimmu.2021.604975

[61]

刘丽婷, 吴利先, 王国富.炎症小体在结核分枝杆菌感染中的作用研究进展[J].中国病原生物学杂志,2019,14(7):857-859, 863.

LIU LT, WU LX, WANG GF.Advances in research on the role of inflammasomes inMycobacterium tuberculosis infection[J].Journal of Pathogen Biology,2019,14(7):857-859, 863 (in Chinese).

[62]

DORHOI A, NOUAILLES G, JÖRG S, HAGENS K, HEINEMANN E, PRADL L, OBERBECK-MÜLLER D, DUQUE-CORREA MA, REECE ST, RULAND J, BROSCH R, TSCHOPP J, GROSS O, KAUFMANN SHE.Activation of the NLRP3 inflammasome byMycobacterium tuberculosisis uncoupled from susceptibility to active tuberculosis[J].European Journal of Immunology,2012,42(2):374-384.

https://doi.org/10.1002/eji.201141548

[63]

GUARDA G, BRAUN M, STAEHLI F, TARDIVEL A, MATTMANN C, FÖRSTER I, FARLIK M, DECKER T, du PASQUIER RA, ROMERO P, TSCHOPP J.Type Ⅰ interferon inhibits interleukin-1 production and inflammasome activation[J].Immunity,2011,34(2):213-223.

https://doi.org/10.1016/j.immuni.2011.02.006

[64]

MAYER-BARBER KD, BARBER DL, SHENDEROV K, WHITE SD, WILSON MS, CHEEVER A, KUGLER D, HIENY S, CASPAR P, NÚÑEZ G, SCHLUETER D, FLAVELL RA, SUTTERWALA FS, SHER A.Cutting edge: caspase-1 independent IL-1β production is critical for host resistance toMycobacterium tuberculosis and does not require TLR signalingin vivo[J].The Journal of Immunology,2010,184(7):3326-3330.

https://doi.org/10.4049/jimmunol.0904189

[65]

ANTONELLI LRV, GIGLIOTTI ROTHFUCHS A, GONÇALVES R, ROFFÊ E, CHEEVER AW, BAFICA A, SALAZAR AM, FENG CG, SHER A.Intranasal Poly-IC treatment exacerbates tuberculosis in mice through the pulmonary recruitment of a pathogen-permissive monocyte/macrophage population[J].Journal of Clinical Investigation,2010,120(5):1674-1682.

https://doi.org/10.1172/JCI40817

[66]

DORHOI A, YEREMEEV V, NOUAILLES G, WEINER J Ⅲ, JÖRG S, HEINEMANN E, OBERBECK-MÜLLER D, KNAUL JK, VOGELZANG A, REECE ST, HAHNKE K, MOLLENKOPF HJ, BRINKMANN V, KAUFMANN SHE.Type Ⅰ IFN signaling triggers immunopathology in tuberculosis-susceptible mice by modulating lung phagocyte dynamics[J].European Journal of Immunology,2014,44(8):2380-2393.

https://doi.org/10.1002/eji.201344219

[67]

YAN SS, SHEN HB, LIAN QS, JIN WL, ZHANG RH, LIN X, GU WP, SUN XY, MENG GX, TIAN ZG, CHEN ZW, SUN B.Deficiency of the AIM2-ASC signal uncovers the STING-driven overreactive response of type Ⅰ IFN and reciprocal depression of protective IFN-γ immunity in mycobacterial infection[J].The Journal of Immunology,2018,200(3):1016-1026.

https://doi.org/10.4049/jimmunol.1701177

[68]

LIAO Y, LIU CF, WANG J, SONG YJ, SABIR N, HUSSAIN T, YAO J, LUO LJ, WANG HR, CUI YY, YANG LF, ZHAO DM, ZHOU XM.Caspase-1 inhibits IFN-β productionvia cleavage of cGAS duringM.bovis infection[J].Veterinary Microbiology,2021,258:109126.

https://doi.org/10.1016/j.vetmic.2021.109126

[69]

YANG L, ZHANG YW, LIU Y, XIE YZ, WENG D, GE BX, LIU HP, XU JF.Pseudomonas aeruginosa induces interferon-β production to promote intracellular survival[J].Microbiology Spectrum,2022,10(5):e0155022.

https://doi.org/10.1128/spectrum.01550-22

[70]

宋敏, 陆普选, 方伟军, 韩远远, 梁瑞云.2022年WHO全球结核病报告: 全球与中国关键数据分析[J].新发传染病电子杂志,2023(1):87-92.

SONG M, LU PX, FANG WJ, HAN YY, LIANG RY.The global tuberculosis report 2022: key data analysis for China and the global world[J].Electronic Journal of Emerging Infectious Diseases,2023(1):87-92 (in Chinese).

[71]

SABIR N, HUSSAIN T, SHAH S, ZHAO DM, ZHOU XM.IFN-β: a contentious player in host-pathogen interaction in tuberculosis[J].International Journal of Molecular Sciences,2017,18(12):2725.

https://doi.org/10.3390/ijms18122725

2024年第64卷第2期

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doi: 10.13343/j.cnki.wsxb.20230416

接收时间：2023-06-14
首发时间：2026-03-18
出版时间：2024-02-04

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收稿日期：2023-06-14
录用日期：2023-08-15

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Zhejiang Provincial Natural Science Foundation(LTGD23C180001)

浙江省自然科学基金(LTGD23C180001)

Fundamental Research Funds for Grant from Zhejiang A&F University(2022LFR067)

浙江农林大学学校科研发展基金(2022LFR067)

Fundamental Research Funds for the Provincial Universities of Zhejiang(2020YQ008)

浙江省属高校基本科研业务费专项基金(2020YQ008)

National Natural Science Foundation of China(32272951)

国家自然科学基金(32272951)

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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