微生物学报

猪丁型冠状病毒拮抗细胞焦亡的研究进展

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孔令贺 , 刘茜倩 , 马婧姣 , 孙建和 , 严亚贤 ^*

微生物学报 | 综述 2024,64(11): 4011-4021

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微生物学报 | 综述 2024, 64(11): 4011-4021

猪丁型冠状病毒拮抗细胞焦亡的研究进展

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孔令贺, 刘茜倩, 马婧姣, 孙建和, 严亚贤^*

作者信息

上海交通大学农业与生物学院, 上海市兽医生物技术重点实验室, 上海 200240

Antagonism of pyroptosis by porcine deltacoronavirus

Linghe KONG, Xiqian LIU, Jingjiao MA, Jianhe SUN, Yaxian YAN^*

Affiliations

Shanghai Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China

出版时间: 2024-09-05 doi: 10.13343/j.cnki.wsxb.20240231

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摘要

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猪丁型冠状病毒(porcine deltacoronavirus, PDCoV)是一种新发现的猪肠道致病性病毒，呈现全球流行趋势，能够引起仔猪腹泻、呕吐、脱水，给养猪业带来重大的经济损失。该病毒具有跨种传播特征，能够感染人类和养殖动物，对动物和人类的健康存在一定的威胁。细胞焦亡是由Gasdermin家族蛋白介导的细胞程序性死亡，在病原感染过程中发挥防御和清除的作用。冠状病毒在长期的进化过程中形成了拮抗焦亡逃逸宿主天然免疫反应的策略。本文对PDCoV的主要生物学特征、细胞焦亡的过程以及PDCoV对Gasdermin D介导的细胞焦亡的拮抗作用进行综述，为深入了解PDCoV拮抗宿主免疫反应的机制以及防控PDCoV的感染提供一定的理论支撑。

关键词

猪丁型冠状病毒 / 焦亡 / Gasdermin D (GSDMD) / 免疫逃避

Abstract

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Porcine deltacoronavirus (PDCoV), an emerging virus globally prevalent, causes watery diarrhea, vomiting, and dehydration of newborn piglets, posing severe economic losses in the swine industry. Moreover, with the characteristic of cross-species transmission, PDCoV can infect human and farmed animals, posing a serious threat to human health. Pyroptosis is a form of programmed cell death mediated by members of the Gasdermin family, which plays a role in defending and eliminating viruses. Coronaviruses, however, have developed precise strategies to antagonize pyroptosis and evade immune responses. This review expounds the biological characteristics of PDCoV, the process of pyroptosis, and the antagonism of Gasdermin D-mediated pyroptosis by PDCoV, aiming to enrich the knowledge about the antagonism of immune responses by PDCoV and lay a theoretical foundation for the prevention and control of this virus.

Key words

porcine deltacoronavirus / pyroptosis / Gasdermin D (GSDMD) / immune escape

引用本文

孔令贺, 刘茜倩, 马婧姣, 孙建和, 严亚贤. 猪丁型冠状病毒拮抗细胞焦亡的研究进展. 微生物学报, 2024 , 64 (11) : 4011 -4021 . DOI: 10.13343/j.cnki.wsxb.20240231

Linghe KONG, Xiqian LIU, Jingjiao MA, Jianhe SUN, Yaxian YAN. Antagonism of pyroptosis by porcine deltacoronavirus[J]. Acta Microbiologica Sinica, 2024 , 64 (11) : 4011 -4021 . DOI: 10.13343/j.cnki.wsxb.20240231

正文

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冠状病毒(coronaviru, CoV)是一类有囊膜的单股正链RNA病毒，是目前已知的含有最长基因组序列的RNA病毒，已在全球范围内流行，对人类和动物的生命安全造成极大威胁^[1]。根据国际病毒分类命名委员会(International Committee on Taxonomy of Viruses, ICTV)的分类，冠状病毒属于套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒亚科(Coronavirinae)，冠状病毒亚科主要分为Alphacoronavirus (αCoV)、Betacoronavirus (βCoV)、Gammacoronavirus (γCoV)以及Deltacoronavirus (δCoV) 4个属^[2]。猪丁型冠状病毒(porcine deltacoronavirus, PDCoV)属于δ冠状病毒，是一类猪肠道致病性冠状病毒，可感染不同年龄段的猪，导致哺乳期仔猪死亡率较高^[3]。PDCoV可以单独感染宿主，也存在与其他猪肠道病毒对宿主产生混合感染的情况^[4]。

细胞焦亡是一类由Gasdermin (GSDM)家族蛋白介导的程序性细胞死亡，宿主细胞识别病原或者其他刺激信号时，Gasdermin家族蛋白通过切割解除自抑制状态，在细胞膜上形成寡聚体孔道诱导细胞死亡，同时释放大量炎症因子，促进机体对病原的清除^[5-7]。病原体为促进自身的感染与增殖，进化出了抑制细胞焦亡的功能，逃逸宿主的天然免疫；冠状病毒基因组编码多种结构蛋白、非结构蛋白和辅助蛋白，某些非结构蛋白具有酶的活性，存在抑制宿主天然免疫的功能^[8]。本文从PDCoV非结构蛋白对宿主细胞焦亡通路关键蛋白的相互作用展开论述，为今后深入了解PDCoV拮抗宿主免疫反应以及开发有效防控PDCoV的疫苗和药物提供理论支撑。

1 猪丁型冠状病毒感染特性

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PDCoV呈现全球性流行的趋势，极大地影响了养猪产业的发展。2012年，Woo等在中国香港首次在猪的肠道内检测到PDCoV^[9]。2014年，美国、韩国及加拿大相继报道检测出PDCoV^{[4, 10-12]}。目前中国已有多个省份相继检测到此病毒，本课题组纪立凯等成功分离到上海地区的流行毒株^[13]。2021年，首次在患病儿童血浆样品中检测到PDCoV^[14]，表明该病毒具有跨物种传播的特征。PDCoV是一类猪肠道致病性病毒，主要通过粪-口传播，引起小肠绒毛脱落、萎缩，造成仔猪腹泻、呕吐、脱水，对仔猪的生存有较大的威胁。成年猪感染PDCoV后，临床症状相对于仔猪较轻^[15-16]。PDCoV是单股正链有囊膜的RNA病毒，其亚显微结构呈现球状或椭圆状，外膜有凸起，整体结构呈现为冠状病毒典型的“皇冠”状。PDCoV的基因组约为25.4 kb，其基因组包括5′非编码区(untranslated region, UTR)、开放阅读框1a/1b、病毒结构蛋白(nucleocapsid, envelope protein, membrane protein, spike protein)基因、辅助蛋白以及3′非编码区^[17-18]。其中1a和1b编码的多聚蛋白pp1a和pp1b可以被加工成15个非结构蛋白(nonstructural proteins, Nsps)^[19-20]。基因组编码的蛋白在病毒的复制和拮抗宿主免疫反应中发挥重要的功能。

病毒受体的相关研究对于病毒感染及跨种传播非常重要。研究表明氨基肽酶N (aminopeptidase N, APN)能够与冠状病毒S蛋白结合，介导病毒感染细胞^[21]。然而APN在PDCoV感染宿主过程中的作用仍处于研究阶段^[22-23]。Zhu等研究发现，使用APN特异性抗体处理回肠细胞系IPI-2I后能够抑制PDCoV的感染；使用APN抑制剂处理细胞后，发现APN的酶活性不影响PDCoV的感染，其表位构象与PDCoV的感染有关；通过构建猪APN敲除的回肠细胞系IPI-2I发现，APN敲除后不能完全阻断PDCoV的感染，但能够影响病毒的复制^[24]。因此APN并非PDCoV感染的唯一受体，关于PDCoV受体的工作仍需要进一步开展。

纪立凯^[25]发现，PDCoV具有体外感染猪源、鸡源和人源细胞系的能力。瞿欢等^[26]发现，PDCoV在感染猪源细胞LLC-PK1、PK15、ST、PAM和猴源细胞Vero后能出现明显的细胞病变效应(cytopathic effect, CPE)，在LLC-PK1、PK15和ST细胞中能够持续传代，此外，还能够感染猪源ZYM-SIEC02、禽源DEF、猴源Marc-145和人源HEK-293细胞，但是不能持续传代。Fang等^[27]研究证明，PDCoV能够感染人源A549、猪源IPAM、牛源MDBK和猴源Vero细胞。这些结果表明PDCoV可以在体外感染不同物种的细胞，存在跨种传播的危险。

2 细胞焦亡的基本特征

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细胞焦亡是由Gasdermin家族蛋白介导的程序性细胞死亡。GSDM家族目前已经报道了GSDMA、GSDMB、GSDMC、GSDMD、GSDME (DFNA5)、DFNB59 (pejvakin)等6种分子，它们在机体内分布于多个组织^[28-29]。除了DFNB59外，均包含GSDM N端成孔区域(GSDM N terminal pore forming fragment, GSDM-NF)和GSDM C端的抑制区域(GSDM C terminal repressor fragment, GSDM-CF)，在生理状态下处于自抑制状态^[30]。Gasdermin D (GSDMD)是首个被发现的焦亡执行蛋白。

焦亡起初是在鼠伤寒沙门菌(Salmonella typhimurium)感染的巨噬细胞中发现的^[31]，依赖于caspase-1同时伴随IL-1β和IL-18炎症因子的释放^[32]。进一步的研究发现，焦亡由病原体相关分子模式(pathogen-associated molecular patterns, PAMPs)和损伤相关的分子模式(danger-associated molecular patterns, DAMPs)引发，PAMPs和DAMPs由模式识别受体(pattern recognition receptor, PRR)识别后，形成由活化后的caspase-1组成的炎症小体复合物^[33]。除了PRR引起的caspase-1炎症小体的组装之外，人源的caspase-4/5以及鼠源的caspase-11能够直接作为PRR和效应蛋白结合胞内的脂多糖(lipopolysaccharides, LPS)进而被活化^[5-6]。当焦亡启动时，活化后的caspase能够切割GSDMD，去掉GSDMD C端的抑制区域，使其由自抑制状态变为活化状态。活化后的GSDMD N端成孔区域(GSDMD N terminal pore forming fragment, GSDMD-NF)暴露出碱性氨基酸位点，该位点与磷酸肌醇磷酸盐(phosphoinositide phosphates)、磷脂酰丝氨酸(phosphatidylserine)、磷脂酸(phosphatidic acid)和心磷脂(cardiolipin)等酸性磷脂结合，促进GSDMD-NF募集到含有这些磷脂的细胞膜，形成寡聚体孔道^[34-36]。孔道的直径为18−22 nm，由31−34个GSDMD-NF组成，最终导致细胞膜快速地出现损伤，释放出胞内的DAMPs以及炎症因子^{[5-7, 37-39]} (图1)。

3 PDCoV拮抗细胞焦亡

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细胞焦亡是宿主天然免疫过程的重要组成部分，有助于清除病原感染的细胞，减少病原体在胞内的存活与增殖，抵御病原微生物对机体的伤害^[40]。GSDMD在小肠中具有较高的表达水平^[41]。猪GSDMD介导的细胞焦亡研究目前处于起步阶段。Song等研究发现猪的GSDMD是caspase-1的底物，介导细胞焦亡^[42]。随后，Song等以及Yang等分别制备了猪GSDMD的抗体，探究了猪GSDMD在不同组织和细胞中的表达情况，为研究猪GSDMD介导的细胞焦亡提供了有效的工具和基础信息^[43-44]。猪的GSDMD在病毒感染过程中发挥着重要的作用。研究表明，猪繁殖与呼吸综合征病毒(porcine reproductive and respiratory syndrome virus, PRRSV)感染猪肺泡巨噬细胞后能够活化NOD样受体家族核苷酸结合寡聚化结构域样受体3 (NOD-like receptor thermal protein domain associated protein 3, NLRP3)炎症小体，引起GSDMD依赖的细胞焦亡和IL-1β的分泌^[45]；猪传染性胃肠炎病毒(transmissible gastroenteritis virus, TGEV)感染猪空肠细胞后能够显著诱导NLRP3依赖的IL-1β的分泌以及GSDMD的活化^[46]；猪瘟病毒(classical swine fever virus, CSFV)感染单核细胞后能够诱导caspase 1介导的IL-1β的表达和加工，并且诱导GSDMD的活化^[47]；伪狂犬病病毒(pseudorabies virus, PRV)在感染猪肺泡巨噬细胞后能够引起GSDMD介导的焦亡，进而导致IL-1β和LDH的释放^[48]。另外，猪GSDMD能够促进抗病毒IFN-β通过非经典途径释放，增强干扰素刺激基因的应答抑制冠状病毒的感染，发挥抗病毒的功能^[49]。

冠状病毒的宿主类型较为广泛，主要对呼吸系统和胃肠消化系统造成损伤，新型冠状病毒(SARS-CoV-2)主要引起呼吸系统疾病，造成肺炎等多脏器损伤^[50]；猪肠道冠状病毒PDCoV、TGEV以及猪流行性腹泻病毒(porcine epidemic diarrhea virus, PEDV)主要感染猪小肠上皮，对新生仔猪产生较高的发病率和死亡率，对养猪产业产生重大的影响^[51]。在感染与免疫的过程中，冠状病毒进化出了多种策略来逃避宿主的免疫反应，应对GSDMD介导的焦亡^[40]。根据目前的报道，PDCoV可能通过抑制上游核因子κB (nuclearfactor-κB, NF-κB)转录因子的活性在转录水平影响炎症小体的激活，从而拮抗GSDMD介导的焦亡；此外，PDCoV编码的病毒蛋白能够在蛋白水平对GSDMD产生直接作用，进而拮抗焦亡的发生。目前PDCoV与GSDMD的研究相对有限，需要进一步深入研究。

3.1 PDCoV通过抑制NF-κB信号拮抗焦亡

GSDMD介导的细胞焦亡经典通路依赖于NLRP3炎症小体的激活。NF-κB是NLRP3炎症小体组分的重要转录因子^[52]。病毒通过抑制NF-κB转录因子的活化对NLRP3炎症小体-GSDMD介导的细胞焦亡也会产生一定程度的抑制作用。研究表明，PDCoV感染后不激活NF-κB启动子的活性，显著抑制仙台病毒(Sendai virus, SeV)诱导的NF-κB启动子的活性，并在一定程度上抑制poly(I: C)诱导的NF-κB启动子的活性^[53]。PDCoV非结构蛋白5 (nonstructural protein 5, Nsp5)能够在谷氨酰胺231 (Q231)位点切割NF-κB信号的重要调节因子NF-κB必需调节剂(NF-κB essential modifier, NEMO)，抑制NF-κB信号(图2)^[54]。此外，有研究报道PDCoV Nsp15能够通过不依赖核糖核酸内切酶活性的方式影响NF-κB的活化(图2)^[55]。这表明PDCoV的非结构蛋白能够在转录水平影响NLRP3炎症小体的激活，通过影响上游信号的激活来抑制GSDMD介导的焦亡。

3.2 PDCoV Nsp5切割GSDMD抑制焦亡

Ma等^[56]研究表明，SARS-CoV-2病毒的N蛋白能够高效地结合GSDMD-NF和GSDM-CF的连接区域，阻碍GSDMD解除自抑制状态，抑制GSDMD介导的焦亡和细胞因子的释放。TGEV的3C样蛋白酶(Nsp5)能够切割GSDMD并形成无功能的N端片段，抑制焦亡^[40]。此外，Shi等^[57]的研究表明，SARS-CoV-2、MERS CoV和PEDV的Nsp5能够在猪GSDMD的Q193−G194区域将GSDMD切割成2个片段，其中N端的片段不能诱导焦亡，同时2个片段均不影响PEDV的复制，PEDV能够利用Nsp5-GSDMD途径抑制细胞焦亡。

PDCoV作为目前唯一感染非禽类且能在体外培养的δ冠状病毒，研究其与宿主的互作，了解其在感染宿主过程中对免疫反应的逃避策略对研发相应的保护性疫苗，高效防控PDCoV具有重要意义。研究表明，PDCoV的Nsp5与SARS-CoV-2、MERS CoV 2和PEDV在序列上具有较高的相似性，催化结构域较为保守，表明功能上具有相似性^[57]。PDCoV Nsp5能够将猪源的GSDMD切割形成无功能的片段，将猪GSDMD 193位的氨基酸Q突变为A后，Nsp5无法切割GSDMD，表明猪GSDMD的Q193是PDCoV Nsp5重要的识别位点^[57]。冠状病毒的Nsp5的组氨酸(His, H)和半胱氨酸(Cys, C)残基对其催化活性起到关键作用(PDCoV H41/C144、SARS-CoV-2 H41/C145、MERS CoV H41/C148、PEDV H41/C144)^[58-60]。分别将PDCoV Nsp5组氨酸和半胱氨酸突变后(H41A和C144A)，其催化活性消失，不能够切割猪的GSDMD^[57]。这表明PDCoV的非结构蛋白能够在蛋白水平对GSDMD产生直接切割作用，使其失活，拮抗细胞焦亡的发生(图3)。本课题组研究发现，PDCoV感染细胞后会导致GSDMD在转录水平表达下调，同时也出现蛋白水平表达下调(未发表)，表明PDCoV编码的蛋白可能抑制GSDMD的表达或者降解GSDMD。

3.3 PDCoV抑制焦亡的其他方式

病原抑制细胞焦亡的方式主要有逃逸炎症小体的识别、抑制炎症小体组装活化、抑制caspase的活性、抑制GSDM的活化以及抑制GSDM-NF形成寡聚体孔道^[61]。翻译后的修饰对GSDMD的活化有重要的调控作用^[38]，病毒有可能通过调控GSDMD翻译后的修饰影响细胞焦亡。目前关于PDCoV抑制细胞焦亡的报道相对有限，其基因组编码的其他蛋白是否对GSDMD介导的焦亡通路产生影响仍然不清楚。PDCoV对GSDMD介导的细胞焦亡的拮抗作用机制需要进一步地深入研究。

4 总结与展望

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PDCoV作为一种新发现的δ属冠状病毒，能感染人类和养殖动物等广泛的宿主，在体外能够感染较多物种的细胞系。当前对于其感染和引起免疫反应的机制研究相对有限，有部分研究介绍了其起源和遗传演化过程、基础的生物学特征以及对宿主天然免疫的影响^{[1, 3, 17-18, 62]}。然而，其致病机理以及拮抗宿主免疫反应的机制仍然需要进一步深入地研究。细胞焦亡作为GSDM家族蛋白介导的程序性细胞死亡，在宿主防御病原感染的过程发挥着重要的作用^[40]。病原感染被模式识别受体识别后，引起NLRP3炎症小体的组装，进而活化GSDMD，形成GSDMD-NF导致细胞发生焦亡并释放大量的炎症因子，从而清除病原体^[45]。病原在与宿主免疫系统的斗争中进化出了抑制细胞焦亡从而促进自身增殖感染的策略^[61]。PDCoV Nsp5能够对自身基因组编码的前体多聚蛋白进行加工，形成非结构蛋白，对病毒的复制至关重要^[54]。Nsp5能直接切割焦亡执行蛋白GSDMD导致其产生不具备诱导焦亡功能的片段抑制细胞焦亡，促进自身的复制^[57]。NF-κB对于NLRP3的转录具有调控作用，影响NLRP3炎症小体的组装。PDCoV的Nsp5能够对NF-κB的调控因子NEMO进行切割，从而抑制NF-κB信号^[54]的激活。另外，PDCoV的Nsp15对NF-κB的活化也有一定的抑制作用^[55]。NF-κB信号受到抑制会对NLRP3的活化产生影响，进而影响NLRP3炎症小体的组装和GSDMD介导的焦亡。

尽管目前已发现PDCoV的Nsp5对细胞的焦亡具有一定的拮抗作用，但PDCoV在逃逸宿主细胞焦亡过程中的机制还有很多未解。PDCoV在拮抗细胞焦亡过程中哪些蛋白发挥关键作用？PDCoV对NLRP3炎症小体的识别组装、GSDMD蛋白的活化以及GSDMD-NF的寡聚化和定位是否有影响？未来关于PDCoV拮抗宿主焦亡的研究可以围绕这些方面深入开展。探究PDCoV拮抗细胞焦亡的作用机制，将为PDCoV的病原学研究和临床治疗与防控提供重要的理论支撑。

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2024年第64卷第11期

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接收时间：2024-04-10
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出版时间：2024-09-05

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上海交通大学农业与生物学院, 上海市兽医生物技术重点实验室, 上海 200240

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https://castjournals.cast.org.cn/joweb/wswxb/CN/10.13343/j.cnki.wsxb.20240231

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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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