病原體逃逸宿主固有免疫的新策略：抑制細(xì)胞焦亡

楊茂藝，崔瀟月，鄭詩棋，馬詩瑤，鄭增長，鄧萬燕

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病原體逃逸宿主固有免疫的新策略：抑制細(xì)胞焦亡

楊茂藝1，崔瀟月2,3，鄭詩棋2，馬詩瑤2，鄭增長4，鄧萬燕2

1. 重慶醫(yī)科大學(xué)感染性疾病分子生物學(xué)教育部重點(diǎn)實(shí)驗(yàn)室，重慶 400010 2. 重慶醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院病原教研室，重慶 400010 3. 遂寧市中心醫(yī)院基礎(chǔ)實(shí)驗(yàn)室，遂寧 629000 4. 同濟(jì)大學(xué)附屬東方醫(yī)院，上海 200120

細(xì)胞焦亡是一種由Gasdermin家族蛋白介導(dǎo)的新型程序性細(xì)胞死亡。當(dāng)宿主細(xì)胞感應(yīng)病原體感染或其他危險(xiǎn)信號時(shí)，Gasdermin家族蛋白被切割活化并誘導(dǎo)細(xì)胞焦亡。細(xì)胞焦亡過程往往伴隨大量炎性細(xì)胞因子釋放，這些炎性細(xì)胞因子在宿主清除病原體過程中發(fā)揮著至關(guān)重要作用，而病原體在與宿主長期“博弈”過程中也進(jìn)化出抑制細(xì)胞焦亡的策略以實(shí)現(xiàn)免疫逃逸。本文介紹了細(xì)胞焦亡的發(fā)現(xiàn)歷程及其在抗感染免疫中的重要功能，并總結(jié)了病原體抑制細(xì)胞焦亡的多種新策略及其相關(guān)研究進(jìn)展。深入理解細(xì)胞焦亡的發(fā)生及調(diào)控機(jī)制，可揭示相關(guān)感染性疾病的發(fā)病機(jī)制并有助于開發(fā)有效的抗感染治療策略。

細(xì)胞焦亡；病原體；效應(yīng)蛋白；免疫逃逸

固有免疫應(yīng)答是宿主識別與抵抗病原體感染的第一道防線，對激活適應(yīng)性免疫進(jìn)而清除病原體至關(guān)重要。位于細(xì)胞膜表面、內(nèi)體或細(xì)胞質(zhì)的模式識別受體(pattern recognition receptor，PRRs)通過識別病原體相關(guān)分子模式(pathogen-associated mole-cular patterns，PAMPs)或宿主損傷相關(guān)分子模式(damage- associated molecular patterns，DAMPs)啟動固有免疫應(yīng)答抑制病原體的感染[1]。作為固有免疫的重要組成部分，細(xì)胞焦亡是一種由Gasdermin (GSDM)家族蛋白活化介導(dǎo)的新型程序性細(xì)胞死亡，在清除內(nèi)源病變或外源感染過程中發(fā)揮關(guān)鍵作用[2～4]。1986年，F(xiàn)riedlander等[5]發(fā)現(xiàn)炭疽致死毒素(lethal toxin)處理小鼠原代巨噬細(xì)胞能夠?qū)е录?xì)胞死亡和細(xì)胞內(nèi)容物的迅速釋放。隨后，Black等[6]在1989年報(bào)道細(xì)胞內(nèi)存在一種可以剪切白介素1β前體(pro-IL-1β)的天冬氨酸蛋白酶，并將其定義為IL-1β轉(zhuǎn)換酶(IL-1β converting enzyme，ICE)。1992年，Thornberry等[7]首次克隆到ICE基因，并發(fā)現(xiàn)ICE蛋白是由p20和p10兩個(gè)亞基構(gòu)成的異二聚體。同年，Zychlinsky等[8]發(fā)現(xiàn)被福氏志賀氏菌()感染的巨噬細(xì)胞存在“自殺”現(xiàn)象。1996年，ICE被重命名為Caspase-1[9]。同年，Chen等[10]進(jìn)一步發(fā)現(xiàn)效應(yīng)蛋白IpaB (invasion plasmid antigen B)直接結(jié)合并活化ICE誘導(dǎo)巨噬細(xì)胞發(fā)生“炎性細(xì)胞凋亡”。Cookson等[11]在2001年首次使用“細(xì)胞焦亡”概念來描述這一炎性細(xì)胞死亡。Martinon等[12]在2002年首次發(fā)現(xiàn)直接激活Caspase-1的蛋白復(fù)合物—炎癥小體(inflammasome)。2015年，北京生命科學(xué)研究所邵峰課題組和美國基因泰克公司Vishva M. Dixit課題組在雜志上背靠背發(fā)表了關(guān)于細(xì)胞焦亡的關(guān)鍵執(zhí)行蛋白Gasdermin D (GSDMD)的研究成果，成為細(xì)胞焦亡研究的里程碑[13,14]。隨后研究人員又陸續(xù)發(fā)現(xiàn)了Gasdermin家族其他成員的內(nèi)源性活化機(jī)制[15]，細(xì)胞焦亡則因此被重新定義為“由Gasdermin家族蛋白介導(dǎo)的程序性細(xì)胞死亡”[13～15]。本文總結(jié)了病原體通過抑制炎癥小體活化或直接靶向Gasdermin家族蛋白活化等策略抑制細(xì)胞焦亡從而逃逸宿主免疫反應(yīng)的分子機(jī)制，討論了以Gasdermin家族蛋白作為治療感染性疾病靶點(diǎn)的前景與挑戰(zhàn)。

1 細(xì)胞焦亡的關(guān)鍵執(zhí)行蛋白：Gasdermins

Gasdermin家族包含六個(gè)成員：GSDMA、GSDMB、GSDMC、GSDMD、GSDME(又稱DFNA5)和PJVK(又稱DFNB59)[16]。除PJVK外，GSDMA-E均由功能保守的N端結(jié)構(gòu)域(GSDM-NT)和C端結(jié)構(gòu)域(GSDM-CT)組成。GSDM-NT能夠結(jié)合細(xì)胞膜酸性磷脂或線粒體心磷脂，并在膜上多聚化形成孔洞以誘導(dǎo)細(xì)胞焦亡[15]。自21世紀(jì)初“焦亡”概念提出以來，大量研究結(jié)果顯示革蘭氏陰性菌主要通過激活炎癥小體(inflammasome)進(jìn)而切割活化GSDMD以觸發(fā)細(xì)胞焦亡[13,17～20]?！把装Y小體”概念由瑞士洛桑大學(xué)生物化學(xué)研究所生物醫(yī)學(xué)研究中心Tschopp課題組首次提出，分為經(jīng)典炎癥小體和非經(jīng)典炎癥小體[12]。經(jīng)典炎癥小體主要由Caspase-1、胞質(zhì)內(nèi)的模式識別受體(NLRP3、NLRC4、NLRP1、AIM2、Pyrin等)和凋亡相關(guān)斑點(diǎn)樣蛋白(Apoptosis-associated Speck-like Protein，ASC)組成[21]。經(jīng)典炎癥小體組裝后激活Caspase-1進(jìn)而切割GSDMD，釋放GSDMD-NT導(dǎo)致細(xì)胞焦亡。與此同時(shí)，Caspase-1切割活化IL-1β和白介素18(IL-18)等促炎癥因子，招募免疫細(xì)胞，清除外源病原體或內(nèi)源病變[15,22]。非經(jīng)典炎癥小體由病原菌感染條件下釋放脂多糖(lipopolysaccharide，LPS)至胞內(nèi)直接結(jié)合并激活Caspase-4/5/11，活化的Caspase-4/5/11切割GSDMD形成具有成孔活性的GSDMD-N端結(jié)構(gòu)域并誘導(dǎo)細(xì)胞焦亡[23]。

近年來，多項(xiàng)研究報(bào)道了不依賴于炎癥小體介導(dǎo)的細(xì)胞焦亡通路的活化機(jī)制。在抗腫瘤免疫方面，邵峰課題組與美國托馬斯杰斐遜大學(xué)基梅爾癌癥中心生物化學(xué)與分子生物學(xué)教研室Emad S. Alnemri課題組相繼報(bào)道細(xì)胞凋亡通路的執(zhí)行蛋白Caspase-3能夠切割GSDME，釋放GSDME-NT，促使細(xì)胞凋亡轉(zhuǎn)變?yōu)榧?xì)胞焦亡[24,25]。此外，美國哈佛大學(xué)醫(yī)學(xué)院附屬波士頓兒童醫(yī)院羅鴻博課題組與瑞士病毒學(xué)與免疫學(xué)研究所Charaf Benarafa 課題組分別報(bào)道了GSDMD能夠被中性粒細(xì)胞彈性蛋白酶(neutrophil elastase，ELANE)和組織蛋白酶G (cathepsin G，CatG)切割活化，引起細(xì)胞焦亡[26,27]。美國哈佛大學(xué)醫(yī)學(xué)院附屬波士頓兒童醫(yī)院Judy Lieberman課題組報(bào)道發(fā)現(xiàn)殺傷細(xì)胞釋放顆粒酶B (granzyme B，GZMB)直接切割腫瘤細(xì)胞GSDME觸發(fā)腫瘤細(xì)胞焦亡，提示靶向GSDME是腫瘤免疫療法的一種潛在的新武器[28]。邵峰課題組發(fā)現(xiàn)細(xì)胞毒性淋巴細(xì)胞分泌的顆粒酶A (granzyme A，GZMA)直接切割腫瘤細(xì)胞GSDMB，揭示了GZMA-GSDMB通路介導(dǎo)的焦亡對腫瘤清除的重要性[29]。美國得克薩斯大學(xué)安德森癌癥中心洪明奇課題組與廈門大學(xué)吳喬課題組相繼報(bào)道Caspase-8剪切GSDMC：一方面，在缺氧的條件下，腫瘤壞死因子(TNF-α)和放線菌酮(cyclohe-ximide，CHX)處理激活了腫瘤細(xì)胞Caspase-8，進(jìn)一步誘導(dǎo)GSMDC的剪切以及細(xì)胞焦亡；另一方面，在腫瘤細(xì)胞中，代謝產(chǎn)物α-酮戊二酸(α-Ketoglutarate，α-Kg)激活細(xì)胞活性氧(reactive oxygen species，ROS)信號導(dǎo)致死亡受體6(death receptor 6，DR6)被氧化，氧化的DR6被內(nèi)化到胞漿中并招募Caspase-8與GSDMC聚集，隨后Caspase-8自激活并切割GSDMC，進(jìn)一步誘發(fā)細(xì)胞焦亡[30,31]。在抗感染免疫方面，美國馬薩諸塞大學(xué)醫(yī)學(xué)院Egil Lien和塔夫茨大學(xué)醫(yī)學(xué)院Alexander Poltorak課題組相繼發(fā)現(xiàn)耶爾森菌()分泌的外膜蛋白J (outer protein J，YopJ)抑制轉(zhuǎn)化生長因子β激活激酶1 (transforming growth factor-β-activated Kinase 1，TAK1)，激活RIPK1/Caspase-8復(fù)合體，活化的Caspase-8切割GSDMD導(dǎo)致細(xì)胞焦亡，但Caspase-8如何被激活還處于未知[32,33]。隨后，中國科學(xué)院上海免疫與感染研究所劉星課題組通過全基因組CRISPR敲除篩選發(fā)現(xiàn)Rag-Ragulator復(fù)合體在耶爾森菌感染介導(dǎo)的細(xì)胞焦亡中發(fā)揮關(guān)鍵作用，揭示了Rag-Ragulator復(fù)合體中RagC招募RIPK1和Caspase-8并通過Lamtor1錨定在溶酶體，促使Complex IIb復(fù)合體(FADD-RIPK1-Caspase-8)完成組裝，RagC GTP酶活性激活Caspase-8觸發(fā)細(xì)胞焦亡[34]。此外，該團(tuán)隊(duì)報(bào)道了由A族鏈球菌(Group A，GAS)感染過程中釋放的效應(yīng)蛋白鏈球菌熱源性外毒素B (pyrogenic exotoxin B，SpeB)，一種胱氨酸蛋白酶，直接剪切宿主GSDMA誘導(dǎo)細(xì)胞焦亡，在限制GAS系統(tǒng)性感染過程中發(fā)揮關(guān)鍵作用[35]。這些研究進(jìn)一步拓展和突出了細(xì)胞焦亡在抗感染和抗腫瘤領(lǐng)域的功能。

2 病原體抑制細(xì)胞焦亡的新策略

病原體在與宿主長期“博弈”過程中進(jìn)化出多種抑制細(xì)胞焦亡的策略(圖1，表1)，主要包括：(1)逃逸炎癥小體識別；(2)重編程病原體自身代謝抑制炎癥小體活化；(3)分泌效應(yīng)蛋白抑制炎性Caspase的活性；(4)抑制Gasdermin的活化；(5)抑制GSDM-NT的成孔功能。

2.1 逃逸炎癥小體識別

現(xiàn)有的報(bào)道表明病原體可從抑制模式識別受體激活和表達(dá)、抑制炎癥小體組裝等方面逃逸宿主炎癥小體識別：2010年，美國耶魯大學(xué)醫(yī)學(xué)院Ruslan Medzhitov課題組研究發(fā)現(xiàn)III型分泌系統(tǒng)(type III secretion system ，T3SS)釋放的毒力因子YopK能夠與T3SS轉(zhuǎn)位蛋白直接相互作用，阻止宿主細(xì)胞對T3SS分泌的效應(yīng)蛋白的識別，抑制NLRP3炎癥小體活化[36]；隨后，美國石溪大學(xué)醫(yī)學(xué)院James B Bliska與美國馬薩諸塞大學(xué)醫(yī)學(xué)院Egil Lien課題組的研究顯示的另一毒力因子YopM能夠直接招募并激活宿主激酶PRK1和PRK2，通過磷酸化修飾負(fù)調(diào)控Pyrin炎癥小體活化[37,38]。2017年，香港大學(xué)生物醫(yī)學(xué)學(xué)院黃建東課題組研究發(fā)現(xiàn)金黃色葡萄球菌()分泌的毒力因子腺苷合成酶A (adenosine synthase，AdsA)能夠抑制NLRP3的激活，降低巨噬細(xì)胞對的殺傷[39]。吉林大學(xué)楊勇軍課題組報(bào)道鼠傷寒沙 門氏菌(serovar Typhi-murium，STm)效應(yīng)蛋白SopB (outer protein B)的肌醇磷酸酶活性在抑制NLRC4的激活中發(fā)揮重要作用[40]。德國馬克斯·普朗克感染生物學(xué)研究所Arturo Zychlinsky課題組的研究表明銅綠假單胞菌(，PA)分泌的綠膿菌素(blue pigment pyocyanin，PCN)通過誘導(dǎo)胞內(nèi)活性氧和氮氧化物(reactive oxygen species and nitrogen oxides，ROS/RNS)的產(chǎn)生進(jìn)而抑制NLRP3炎癥小體的活化[41]。英國倫敦帝國理工學(xué)院Gad Frankel與加拿大麥克馬斯特大學(xué)Brian K Coombes課題組的研究表明STm 可以下調(diào)其鞭毛的表達(dá)，以逃避NLRC4的識別，而甲型副傷寒沙門氏菌(，SPtA)產(chǎn)生超長的LPS O-抗原鏈，能夠干擾多種炎癥小體的激活[42,43]。2023年，美國哈佛大學(xué)醫(yī)學(xué)院Benjamin E Gewurz課題組的最新研究表明EB病毒(Epstein-Barr virus，EBV)能夠通過類泛素化修飾其編碼的G蛋白偶聯(lián)受體BILF1以抑制線粒體抗病毒信號蛋白(mitochondrial antiviral-signaling protein，MAVS)介導(dǎo)的NLRP3炎癥小體活化[44]。美國新墨西哥大學(xué)Vojo Deretic課題組在2008年研究發(fā)現(xiàn)結(jié)核分枝桿菌(MTB)通過NLRC4激活Caspase-1，這一過程被鋅金屬蛋白酶(Zn2+metalloprotease，ZMP1)所抑制，但ZMP1如何作用的確切細(xì)節(jié)尚不清楚[45]。美國北卡羅來納大學(xué)萊恩伯格綜合癌癥中心Blossom Damania課題組的研究表明卡波西肉瘤相關(guān)皰疹病毒(Kaposi’s sarcoma-associated herpesvirus，KSHV) ORF63蛋白與人NLRP1同源，該蛋白能夠直接與NLRP1相互作用，通過抑制NLRP1寡聚化以及NLRP1與Pro-caspase-1結(jié)合來阻止炎癥小體的組裝[46]。根據(jù)美國馬里蘭大學(xué)醫(yī)學(xué)院Joao HF Pedra課題組的報(bào)道，在立克次體()感染過程中，蜱蟲唾液中的效應(yīng)蛋白唾液抑素L2與磷脂結(jié)合蛋白膜聯(lián)蛋白A2結(jié)合阻斷NLRC4炎癥小體寡聚化，抑制了下游Caspase-1的激活以及細(xì)胞因子的釋放[47]。日本愛知醫(yī)科大學(xué)醫(yī)學(xué)院Takashi Yokochi課題組發(fā)現(xiàn)仙臺病毒(Sendai Virus) V蛋白通過與NLRP3相互作用，抑制NLRP3-ASC的結(jié)合和隨后ASC寡聚從而破壞NLRP3炎癥小體復(fù)合物的組裝[48]。墨西哥國立理工大學(xué)Vianney Ortiz-Navarrete課題組研究發(fā)現(xiàn)STmT3SS可通過誘導(dǎo)轉(zhuǎn)錄共激活因子Yes相關(guān)蛋白(yes-associated protein，YAP)磷酸化及其與造血細(xì)胞激酶(hemato-poietic cell kinase，HCK)的相互作用來阻止YAP易位到細(xì)胞核，p73/YAP不再結(jié)合到NLRC4啟動子區(qū)，導(dǎo)致NLRC4表達(dá)下調(diào)[49]。蘇州大學(xué)吳淑燕課題組發(fā)現(xiàn)了STm質(zhì)粒毒力因子C (Plasmid Virulence C，SpvC)通過下調(diào)NLRP3和NLRC4的表達(dá)以抑制炎癥小體活化并加劇全身性感染[50]。干擾宿主炎癥小體對病原體的識別已經(jīng)成為細(xì)菌發(fā)生免疫逃逸的新策略，對于增強(qiáng)細(xì)菌的毒力并建立有效的感染至關(guān)重要。靶向該免疫逃逸策略的治療方案的開發(fā)將有助于在固有免疫應(yīng)答早期限制感染的程度，阻止病原體擴(kuò)散。

圖1 病原體抑制細(xì)胞焦亡的新策略

圖繪制網(wǎng)址：https://www.biorender.com/。

2.2 重編程病原體代謝

華東理工大學(xué)陽大海課題組發(fā)現(xiàn)在感染巨噬細(xì)胞的過程中，殺魚愛德華氏菌()激活自身精氨酸代謝途徑，招募宿主細(xì)胞的多胺轉(zhuǎn)運(yùn)系統(tǒng)，將細(xì)胞質(zhì)內(nèi)的精氨酸轉(zhuǎn)化成精胺，導(dǎo)致宿主細(xì)胞質(zhì)內(nèi)精胺積累，阻斷鉀離子外流，抑制NLRP3炎癥小體的激活[51]。美國賓夕法尼亞大學(xué)Igor E. Brodsky課題組通過轉(zhuǎn)座子突變庫篩選發(fā)現(xiàn)STmTCA循環(huán)中介導(dǎo)NLRP3炎癥小體免疫逃逸的基因——烏頭酸酶，該基因的缺失導(dǎo)致NLRP3炎癥小體的快速激活，提示通過操縱氧化代謝逃逸NLRP3炎癥小體[52]。美國加州大學(xué)David M. Underhill課題組發(fā)現(xiàn)通過化學(xué)修飾其細(xì)胞壁組分肽聚糖(PGN)，使其能夠抵御溶酶體的消化，抑制NLRP3炎癥小體激活以及破壞IL-1β的分泌[53]。LPS的結(jié)構(gòu)中脂質(zhì)A能夠被Caspase-11所識別，而病原菌通過不同的策略改變LPS脂質(zhì)A結(jié)構(gòu)逃逸這一過程。 Vinogradov等[54]與Hagar等[55]的研究顯示新兇手弗朗西斯菌()通過乙酰化修飾脂質(zhì)A，逃避了Caspase-11的識別，而脂質(zhì)A能夠發(fā)生脫酰化形成Caspase無法識別的四酰脂質(zhì)A。未來的研究將致力于探尋能夠調(diào)控代謝以發(fā)生免疫逃避的病原體，并確定是否涉及其他細(xì)菌代謝物。針對該免疫逃逸策略的進(jìn)一步研究可以為開發(fā)基于病原體代謝系統(tǒng)抑制劑的抗菌策略開辟道路。

2.3 抑制炎性Caspase的活化

多項(xiàng)研究顯示病原體分泌的效應(yīng)蛋白能夠直接與Caspase相互作用并抑制其活性從而阻斷炎癥小體介導(dǎo)的細(xì)胞焦亡。美國耶魯大學(xué)醫(yī)學(xué)院Richard A Flavell課題組研究發(fā)現(xiàn)T3SS分泌的細(xì)胞外酶U (exoenzyme U，ExoU)通過其A2磷脂酶活性抑制Caspase-1的激活[56]。Jakka等[57]發(fā)現(xiàn)布魯氏菌()編碼的一種含TIR結(jié)構(gòu)域的效應(yīng)蛋白(TIR domain-containing protein encoded by Brucella，TcpB )能夠與Caspase-1/4/11相互作用并促進(jìn)Caspase-1/4/11的泛素化和降解，抑制Caspase-1/4/11介導(dǎo)的炎癥信號轉(zhuǎn)導(dǎo)。英國帝國理工學(xué)院Gad Frankel課題組發(fā)現(xiàn)腸致病性大腸桿菌(Enteropathogenic Escherichia coli，EPEC)和腸出血性大腸桿菌(Enterohemorrhagic E. coli，EHEC)T3SS效應(yīng)蛋白non-LEE encoded effector F(NleF)直接結(jié)合并通過干擾Caspase-4/11不同亞基的多聚化從而抑制其蛋白酶活性[58,59]。日本東京大學(xué)Chihiro Sasakawa課題組發(fā)現(xiàn)福氏志賀菌()外膜蛋白C3(outer Shigella proteins C3，OspC3)也具有與NleF類似的作用機(jī)制[60]。邵峰課題組進(jìn)一步研究揭示了OspC3通過ADP-核糖基化修飾Caspase-4/11并使其失活來實(shí)現(xiàn)對非經(jīng)典炎癥小體活化的抑制[61]。此外，英國劍橋大學(xué)Felix Randow和邵峰課題組相繼研究發(fā)現(xiàn)侵襲質(zhì)粒抗原H (invasion plasmid antigen H 9.8，IpaH9.8)通過泛素化并降解鳥苷酸結(jié)合蛋白1-4 (guanylate binding proteins 1-4，GBP1-4)，使得病原體被限制在囊泡內(nèi)，無法將LPS釋放到胞質(zhì)中[62,63]。圣保羅大學(xué)Dario S. Zamboni課題組發(fā)現(xiàn)由伯氏考克斯體() Dot/ICM IV型分泌系統(tǒng)分泌的效應(yīng)蛋白—半胱天冬酶活性抑制蛋白A (inhibition of Caspase activation，IcaA)同樣能夠抑制Caspase-11的激活[64]。美國康涅狄格大學(xué)Sivapriya Kailasan Vanaja課題組研究顯示EHEC噬菌體編碼的毒力因子志賀毒素(toxin，STX)能夠抑制LPS誘導(dǎo)的非經(jīng)典炎癥小體的激活，且該過程依賴于STX2的催化活性[65]。但上述兩項(xiàng)研究的具體作用機(jī)制尚不清晰。分泌毒力因子抑制炎癥性Caspase 的活化是病原體免疫逃逸的重要策略，發(fā)掘具有該逃逸策略的病原體并進(jìn)一步明確其逃逸機(jī)制將為宿主-病原體相互作用的研究以及相關(guān)感染性疾病的治療提供新的見解。

2.4 抑制Gasdermin的活化

Gasdermin家族蛋白是細(xì)胞焦亡的關(guān)鍵執(zhí)行蛋白，病原體可以直接抑制該家族蛋白的活性和表達(dá)而抑制細(xì)胞焦亡[66,67]。北京大學(xué)夏朋延課題組的研究表明新型冠狀病毒(SARS-CoV-2)核衣殼能夠直接結(jié)合GSDMD-NT和GSDMD-CT之間的連接區(qū)，保護(hù)GSDMD免受Caspase-1的切割從而抑制細(xì)胞焦亡[66]。中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)學(xué)院王建偉課題組研究發(fā)現(xiàn)腸病毒71型(enterovirus，EV71)分泌的蛋白酶3C能夠識別并切割GSDMD的Q193位點(diǎn)，剪切所形成的GSDMD-N端結(jié)構(gòu)域不具備成孔功能，從而抑制細(xì)胞焦亡[67]。美國基因泰克公司Vishva M. Dixit課題組研究表明T3SS效應(yīng)蛋白IpaH7.8能夠識別并泛素化人源的GSDMD使其被蛋白酶體降解[68]。此外，美國德克薩斯大學(xué)Neal M. Alto課題組使用泛素激活的相互作用捕獲技術(shù)(ubiquitin- activated interaction traps，UBAITs)證明IpaH7.8同樣識別宿主GSDMB，能夠通過降解GSDMB有效阻止自然殺傷細(xì)胞清除上皮細(xì)胞中的[69,70]。上述研究豐富了病原體對抗宿主防御系統(tǒng)的機(jī)制，針對該免疫逃逸機(jī)制的研究對靶向病原體分泌蛋白的抑制劑的開發(fā)具有重要價(jià)值。

2.5 抑制GSDM-NT的成孔功能

泛素化是一種能夠調(diào)節(jié)多種細(xì)胞功能的翻譯后修飾，由活化酶 E1，結(jié)合酶E2和連接酶E3催化完成[71]。泛素化不僅能夠靶向底物蛋白以26S 蛋白酶體依賴的方式使其降解，還在調(diào)節(jié)先天性和適應(yīng)性免疫反應(yīng)以及免疫耐受方面具有關(guān)鍵作用。一些病原體已進(jìn)化出復(fù)雜的機(jī)制以逃避或抵消泛素依賴的宿主反應(yīng)，其中由病原體編碼的E3泛素連接酶和去泛素化酶在病原體-宿主細(xì)胞相互作用中發(fā)揮至關(guān)重要的作用[72,73]。中國科學(xué)院微生物研究所劉翠華團(tuán)隊(duì)的研究表明MTB能夠通過劫持泛素來改變宿主膜的磷脂組成以抑制細(xì)胞焦亡：MTB分泌的蛋白質(zhì)酪氨酸磷酸酶B (protein tyrosine phosphatase B，PtpB)通過泛素結(jié)合依賴的方式使宿主細(xì)胞膜磷脂酰肌醇-4-磷酸(PI4P)和磷脂酰肌醇-(4,5)-二磷酸[PI(4,5)P2]去磷酸化，導(dǎo)致 GSDM-NT無法在細(xì)胞膜上成孔從而抑制細(xì)胞焦亡，促進(jìn)其在巨噬細(xì)胞內(nèi)的存活[74]。泛素系統(tǒng)介導(dǎo)的宿主-病原體相互作用為抗感染治療提供了潛在的選擇。

3 結(jié)語與展望

細(xì)胞焦亡是機(jī)體抵抗病原體感染的一種重要天然免疫反應(yīng)，而病原體在宿主免疫系統(tǒng)的壓力下進(jìn)化出了適應(yīng)性策略來抑制細(xì)胞焦亡以實(shí)現(xiàn)持續(xù)感染。本綜述重點(diǎn)總結(jié)了病原體(包括病原菌和病毒)抑制細(xì)胞焦亡的研究進(jìn)展，并討論了病原體及其表達(dá)的毒力因子通過逃逸炎癥小體識別或阻止炎癥小體的組裝與激活、降解Gasdermin家族蛋白以及破壞其細(xì)胞膜成孔功能等方式抑制宿主細(xì)胞焦亡發(fā)生的機(jī)制。

病原體逃逸細(xì)胞焦亡的相關(guān)研究有助于進(jìn)一步了解病原體-宿主相互作用機(jī)制，為開發(fā)新型抗感染治療策略奠定了重要理論基礎(chǔ)。這些研究為感染性疾病提供幾種潛在的治療策略：(1)通過靶向病原體分泌系統(tǒng)的抑制劑，破壞其逃逸細(xì)胞焦亡效應(yīng)因子的釋放來限制病原體的感染[76]。近年來，針對病原體T3SS系統(tǒng)的抑制劑發(fā)展迅速。T3SS復(fù)合物的關(guān)鍵作用蛋白PcrV已在動物模型中得到有效驗(yàn)證可以作為的免疫預(yù)防靶標(biāo)[77]。目前正在研發(fā)的抗PcrV制劑(KB001)已進(jìn)入IIa期臨床試驗(yàn)[78,79]；此外，PcrV/Psl雙特異性人單克隆抗體MEDI3902目前處于IIb期臨床試驗(yàn)階段[80]；(2)通過在感染過程中特異性激活細(xì)胞焦亡實(shí)現(xiàn)對病原體的清除[81]。有研究表明在膿毒癥早期，細(xì)胞焦亡具有保護(hù)性作用[82,83]，適當(dāng)?shù)募?xì)胞焦亡可通過破壞被感染的細(xì)胞促進(jìn)病原體的釋放從而募集免疫細(xì)胞來激活宿主免疫反應(yīng)，促進(jìn)病原體的清除和機(jī)體對感染的抵抗。有研究表明，在膿毒癥早期進(jìn)行谷氨酰胺的預(yù)防性給藥可以促進(jìn)肝細(xì)胞焦亡從而增強(qiáng)對病原體的清除效果[84]；(3)細(xì)胞焦亡的代謝調(diào)控為感染性疾病的治療提供新的前景[85]，基于在感染過程中由病原體自身或感染的宿主代謝重編程特點(diǎn)，通過改變相應(yīng)代謝途徑或代謝物以促進(jìn)細(xì)胞焦亡來控制病原體的感染。盡管如此，這些策略在臨床中的應(yīng)用仍面臨巨大挑戰(zhàn)，如正常細(xì)胞被異常激活細(xì)胞焦亡從而導(dǎo)致炎性因子風(fēng)暴。

表1 病原體抑制細(xì)胞焦亡的新策略

雖然人們在發(fā)現(xiàn)病原體應(yīng)對宿主防御機(jī)制的對策或逃避策略方面已取得顯著進(jìn)展，但對于這一領(lǐng)域的認(rèn)知尚不夠深入，可能存在其他未知的逃逸宿主細(xì)胞焦亡的病原體或機(jī)制。未來的研究應(yīng)繼續(xù)致力于發(fā)掘具有逃逸宿主細(xì)胞焦亡的病原體并闡明細(xì)胞內(nèi)病原體的免疫逃逸機(jī)制，為靶向宿主細(xì)胞焦亡的藥物開發(fā)提供新思路，并為設(shè)計(jì)新型疫苗和治療方案以應(yīng)對感染性疾病奠定重要基礎(chǔ)。

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Inhibiting pyroptosis: novel immune evasion strategies for pathogens

Maoyi Yang1, Xiaoyue Cui2,3, Shiqi Zheng2, Shiyao Ma2, Zengzhang Zheng4, Wanyan Deng2

Pyroptosis is a type of programmed cell death mediated by the Gasdermin family. It is triggered in response to pathogen infection or other danger signals. The activation of Gasdermins leads to pyroptosis and the release of large amounts of inflammatory cytokines. Pyroptosis plays a crucial role in combating pathogen infections, as it helps to eliminate infected cells and activate the immune system. However, pathogens have already developed sophisticated strategies to evade or inhibit pyroptosis, allowing them to persist and facilitate infection. This review provides an overview of the discovery of pyroptosis and its importance in anti-infectious immunity. We also discuss several new strategies for inhibiting pyroptosis by pathogens. A thorough learning of the occurrence and regulation of pyroptosis may reveal the pathogenesis of related infectious diseases and contribute to developing effective anti-infective therapeutic strategies.

pyroptosis; pathogen; effector protein; immune evasion

2023-07-18;

2023-10-18;

2023-11-02

重慶市自然科學(xué)基金創(chuàng)新發(fā)展聯(lián)合基金(編號：CSTB2022NSCQ-LZX0031)資助[Sponsored by the Natural Science Foundation of Chongqing, China (No. CSTB2022NSCQ-LZX0031)]

楊茂藝，碩士研究生，專業(yè)方向：臨床檢驗(yàn)診斷學(xué)。E-mail: yang9910150028@163.com

鄧萬燕，博士，研究員，研究方向：宿主-病原體相互作用。E-mail: dengwanyan@cqmu.edu.cn

鄭增長，博士，副研究員，研究方向：天然免疫激活與調(diào)控。E-mail: zhengzengzhang@126.com

10.16288/j.yczz.23-191

(責(zé)任編委: 謝建平)