微生物学报

Virus	Classification	Viral effector	Mediated signaling	References
African swine fever virus (ASFV)	Viral pro survival BCL-2 proteins	A179L	MOMP	[37]
Pseudorabies virus	gM	MOMP	[38]
γ-herpesviruses 68	M11	MOMP	[39-40]
Adenovirus	E1B19K	MOMP	[41]
Epstein-Barr virus	BHRF1	MOMP	[42-43]
Kaposi’s sarcoma-associated herpesvirus	Ks-Bcl-2	MOMP	[44]
Türkiye herpesvirus	vNr-13	MOMP	[45]
Orfvirus	ORFV125	MOMP	[46]
Hepatitis B virus	HBx	MOMP	[47]
Grouper iridovirus	GIV66	MOMP	[48]
Myxoma virus	M11L	MOMP	[49]
Vaccinia virus	F1L	MOMP	[50]
Ectromelia virus	EMV025	MOMP	[51]
Sheeppox virus	SPPV14	MOMP	[52]
Deerpox virus	DPV022	MOMP	[53]
Fowlpox virus	FPV029	MOMP	[54]
Canarypox	CNP058	MOMP	[55]
Tanapoxvirus	TANV16L	MOMP	[56]
HIV-1	Death receptor activator	Tat/Env/Vpu/gp120	Fas, TNF-R	[21,57]
HCV	Core protein	Fas, TNF-R	[58]
Epstein-Barr virus	LMP2A/LMP1	Fas	[59-60]
Lyssavirus	Matrix protein	TRAIL-R	[61]
γ-herpesviruses	Death receptor inhibitor	vFLIP	DISC	[62]
Molluscum contagiosum virus	MC159	DISC	[63]
HPV	E6	DISC	[28]
Poxvirus	Caspase inhibitor	Serpin	Caspase	[64]
Baculovirus	P35	Caspase	[34]
Virus	IAP	Caspase	[36]

Virus	Classification	Viral effector	Mediated signaling	References
African swine fever virus (ASFV)	Viral pro survival BCL-2 proteins	A179L	MOMP	[37]
Pseudorabies virus	gM	MOMP	[38]
γ-herpesviruses 68	M11	MOMP	[39-40]
Adenovirus	E1B19K	MOMP	[41]
Epstein-Barr virus	BHRF1	MOMP	[42-43]
Kaposi’s sarcoma-associated herpesvirus	Ks-Bcl-2	MOMP	[44]
Türkiye herpesvirus	vNr-13	MOMP	[45]
Orfvirus	ORFV125	MOMP	[46]
Hepatitis B virus	HBx	MOMP	[47]
Grouper iridovirus	GIV66	MOMP	[48]
Myxoma virus	M11L	MOMP	[49]
Vaccinia virus	F1L	MOMP	[50]
Ectromelia virus	EMV025	MOMP	[51]
Sheeppox virus	SPPV14	MOMP	[52]
Deerpox virus	DPV022	MOMP	[53]
Fowlpox virus	FPV029	MOMP	[54]
Canarypox	CNP058	MOMP	[55]
Tanapoxvirus	TANV16L	MOMP	[56]
HIV-1	Death receptor activator	Tat/Env/Vpu/gp120	Fas, TNF-R	[21,57]
HCV	Core protein	Fas, TNF-R	[58]
Epstein-Barr virus	LMP2A/LMP1	Fas	[59-60]
Lyssavirus	Matrix protein	TRAIL-R	[61]
γ-herpesviruses	Death receptor inhibitor	vFLIP	DISC	[62]
Molluscum contagiosum virus	MC159	DISC	[63]
HPV	E6	DISC	[28]
Poxvirus	Caspase inhibitor	Serpin	Caspase	[64]
Baculovirus	P35	Caspase	[34]
Virus	IAP	Caspase	[36]

Bacterium	Effector	Targeted pathway	Mediated signaling	References
Shigella flexneri	VirA	P53	P53	[66-67]
IpgD	PI3K/Akt	PI3K/Akt	[87-88]
OspZ	TAB2/3, IkB	NF-κB, transcription	[89]
Salmonella enterica	SopB/SigD	PDK1/Rictor	PI3K/Akt	[70,90]
SseK1, SseK 2, SseK 3	TRADD	NF-κB	[91-92]
Legionella pneumophila	LegK1, LnaB	IκBα	NF-κB	[74,93]
SidF	BCL-2	MOMP	[94]
LegK3	Caspase 3, Caspase 7, Caspase 9	Caspase	[86]
LPS O-antigen	Caspase	Caspase	[85]
Chlamydia trachomatis	CPAF	BH-3 only	MOMP	[75]
OmpA	Bax/Bak	MOMP	[81]
CT622	Unknow	MAPK	[95]
Yersinia pseudotuberculosis	YopJ	ERK/p38/JNK	NF-κB, MAPK	[75]
YopK	Unknow	Extrinsic	[96]
Vibrio parahaemolyticus	VopA	MAPKKs	MAPK	[76]
Coxiella burnetii	AnkG	P32	Intrinsic	[77,97]
CaeA	Unknown	Intrinsic/extrinsic	[98]
Mycobacterium tuberculosis	MPT64	BCL-2	MOMP	[73]
Rv0355c	BAK	MOMP	[79]
Rv2387	Caspase 3, Caspase 8	Caspase	[99]
ESAT-6	Caspase 3, Caspase 8	ROS/MAPK-Caspase	[99]
Neisseria meningitidis	PorB	BCL-2	MOMP	[82]

Bacterium	Effector	Targeted pathway	Mediated signaling	References
Shigella flexneri	VirA	P53	P53	[66-67]
IpgD	PI3K/Akt	PI3K/Akt	[87-88]
OspZ	TAB2/3, IkB	NF-κB, transcription	[89]
Salmonella enterica	SopB/SigD	PDK1/Rictor	PI3K/Akt	[70,90]
SseK1, SseK 2, SseK 3	TRADD	NF-κB	[91-92]
Legionella pneumophila	LegK1, LnaB	IκBα	NF-κB	[74,93]
SidF	BCL-2	MOMP	[94]
LegK3	Caspase 3, Caspase 7, Caspase 9	Caspase	[86]
LPS O-antigen	Caspase	Caspase	[85]
Chlamydia trachomatis	CPAF	BH-3 only	MOMP	[75]
OmpA	Bax/Bak	MOMP	[81]
CT622	Unknow	MAPK	[95]
Yersinia pseudotuberculosis	YopJ	ERK/p38/JNK	NF-κB, MAPK	[75]
YopK	Unknow	Extrinsic	[96]
Vibrio parahaemolyticus	VopA	MAPKKs	MAPK	[76]
Coxiella burnetii	AnkG	P32	Intrinsic	[77,97]
CaeA	Unknown	Intrinsic/extrinsic	[98]
Mycobacterium tuberculosis	MPT64	BCL-2	MOMP	[73]
Rv0355c	BAK	MOMP	[79]
Rv2387	Caspase 3, Caspase 8	Caspase	[99]
ESAT-6	Caspase 3, Caspase 8	ROS/MAPK-Caspase	[99]
Neisseria meningitidis	PorB	BCL-2	MOMP	[82]

胞内寄生病原调控宿主细胞凋亡研究进展

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冉茂双 ¹^,² , 包佳玲 ¹^,² , 潘国庆 ¹^,²^,^*

微生物学报 | 综述 2025,65(11): 4827-4841

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微生物学报 | 综述 2025, 65(11): 4827-4841

胞内寄生病原调控宿主细胞凋亡研究进展

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冉茂双¹^,², 包佳玲¹^,², 潘国庆¹^,²^,^*

作者信息

1 西南大学，资源昆虫高效养殖与利用全国重点实验室，重庆

2 西南大学，微孢子虫感染与防控重庆市重点实验室，重庆

Research progress in the regulation of host cell apoptosis by intracellular pathogens

Maoshuang RAN¹^,², Jialing BAO¹^,², Guoqing PAN¹^,²^,^*

Affiliations

1 State Key Laboratory of Resource Insects, Southwest University, Chongqing, China

2 Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China

出版时间: 2025-11-04 doi: 10.13343/j.cnki.wsxb.20250357

文章导航

摘要

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在多细胞生物中细胞死亡始终处于动态变化的过程。其中，细胞凋亡作为调节性细胞死亡的重要形式主要有内源性和外源性2条通路。在病原感染过程中，宿主细胞可通过细胞凋亡清除被感染的细胞；而病原体也进化出多种策略来调控宿主细胞凋亡，包括利用效应蛋白调控细胞信号通路、凋亡相关基因的表达、凋亡通路关键蛋白以及半胱氨酸蛋白水解酶(cysteinyl aspartate specific proteinase, Caspase)家族蛋白酶活性等。本文对病毒、胞内细菌、胞内寄生真菌以及寄生虫等胞内寄生病原调控宿主细胞凋亡的分子机制与策略进行了综述，以期为进一步探索病原体与宿主之间复杂的相互作用机制提供参考。

关键词

细胞凋亡 / 胞内寄生病原 / 宿主细胞 / 调控机制

Abstract

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In multicellular organisms, cell death is perpetually in a dynamic process. Apoptosis as a pivotal form of regulated cell death, mainly encompasses two pathways: the intrinsic pathway and the extrinsic pathway. During the pathogen infection, host cells are capable of eliminating the infected cells through apoptosis. On the other hand, pathogens have evolved a multitude of strategies to regulate host cell apoptosis. These strategies involve the use of effector proteins to modulate cellular signaling pathways, the regulation of the expression of apoptosis-related genes, the control of key proteins within the apoptosis pathway, and the modulation of the activity of proteases in the Caspase family. This article provides a comprehensive review of the molecular mechanisms and strategies by which intracellular pathogens, such as viruses, bacteria, parasitic fungi, and parasites, regulate host cell apoptosis. The aim is to offer valuable references for further exploration of the intricate interaction mechanisms between pathogens and hosts.

Key words

apoptosis / intracellular pathogens / host cells / regulatory mechanisms

引用本文

冉茂双, 包佳玲, 潘国庆. 胞内寄生病原调控宿主细胞凋亡研究进展. 微生物学报, 2025 , 65 (11) : 4827 -4841 . DOI: 10.13343/j.cnki.wsxb.20250357

Maoshuang RAN, Jialing BAO, Guoqing PAN. Research progress in the regulation of host cell apoptosis by intracellular pathogens[J]. Acta Microbiologica Sinica, 2025 , 65 (11) : 4827 -4841 . DOI: 10.13343/j.cnki.wsxb.20250357

正文

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细胞死亡在多细胞生物中时刻都在发生，通过消除受损或衰老的细胞来维持发育过程中的形态发生和机体稳态，还可通过清除被感染的细胞来限制病原体传播^[1]。细胞可能因意外细胞死亡(accidental cell death, ACD)或调节性细胞死亡(regulated cell death, RCD)而死亡^[2]。ACD是一个不受控制的细胞死亡过程，由意外伤害刺激触发，且超出了细胞的可调节能力，最终导致细胞死亡^[3]。RCD涉及效应分子参与的信号级联反应，具有独特的生化特征、形态特征和免疫学后果；其中，发生在生理条件下的RCD也被称为程序性细胞死亡(programmed cell death, PCD)^[4]。细胞死亡命名委员会制定了从形态学、生化和功能角度定义和解释细胞死亡的指南，目前已定义超过15种细胞死亡类型；例如，细胞凋亡(apoptosis)被定义为由半胱氨酸蛋白水解酶(cysteinyl aspartate specific proteinase, Caspase, 包括起始和效应Caspase)介导的RCD，只有当细胞决定死亡时才会激活效应Caspase，一旦激活细胞死亡不可逆转，最多只能被延迟^[5]。其他类型的细胞死亡包括坏死性凋亡(necroptosis)、细胞焦亡(pyroptosis)、铁死亡(ferroptosis)、自噬(autophagy)、坏死(necrosis)、泛凋亡(panoptosis)、铜死亡(cuproptosis)以及细胞内碱化死亡(alkaliptosis)等^[6]。

在病原微生物与宿主的博弈过程中宿主细胞经调节性细胞死亡后被吞噬细胞吞噬，从而清除被病原体感染的细胞，消除病原体的“生存环境(living niche)”^[7]。然而，随着宿主与病原体相互作用的不断进化，病原体也获得了多种策略来精细调控宿主细胞凋亡。近年来，生命科学研究的进步极大地拓展了病原-宿主相互作用研究的广度和深度，但仍有很多病原操纵宿主细胞的分子机制有待解析。本综述总结了细胞凋亡通路及胞内病原微生物调控宿主细胞凋亡的主要策略，以期为解析胞内病原体通过调控宿主细胞凋亡以促进自身感染和复制的机制提供参考。

1 细胞凋亡通路

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1.1 内源性凋亡通路

内源性凋亡通路又称线粒体凋亡通路，主要是因为该通路的启动信号源自细胞内部的线粒体。当细胞受到DNA损伤、缺氧、代谢应激等刺激时，线粒体外膜透化(mitochondrial outer membrane permeabilization, MOMP)，导致线粒体膜间腔中的蛋白质(如细胞色素C等)被释放到细胞质中，与凋亡蛋白激活因子1 (apoptotic protease activating factor 1, Apaf1)结合并形成凋亡小体，进而激活Caspase 9使下游效应Caspase 3和Caspase 7激活并切割底物等，最终引发细胞凋亡^[8-9]。MOMP受B细胞淋巴瘤-2 (B cell lymphoma 2, BCL-2)家族蛋白的严格调控，根据其在凋亡通路中的作用，BCL-2家族蛋白可分为促凋亡和抗凋亡蛋白两类，不同成员通过调控MOMP发挥作用；例如，在人类中含有多BCL-2同源结构域(BCL-2 homology domain, BH)的抗凋亡蛋白[如BCL-2、BCL-2类蛋白1 (BCL-2 like protein 1, BCL-2L1，也称BCL-XL)、BCL-2类蛋白2 (BCL-2 like protein 2, BCL-2L2，也称BCL-W)、髓样细胞白血病1(mast cell leukemia 1, MCL1)、BCL-2相关蛋白A1 (BCL2-related protein A1, BCL-2A1)和BCL-2类蛋白10 (BCL2-like protein 10, BCL-2L10，也称BCL-B]；含多BH结构域的促凋亡蛋白[如BCL-2同源拮抗剂K (BCL-2 associated K protein, BAK)、BCL-2同源拮抗剂X (BCL-2 associated X protein, BAX)和BCL-2相关卵巢杀伤蛋白(BCL-2-related ovarian killer protein, BOK)]和仅含BH3结构域的促凋亡蛋白[如BH3相互作用域死亡激动剂(BH3-interacting domain death agonist, BID)、BCL-2相互作用介质(BCL-2 interacting mediator, BIM)、BCL-2相关的细胞死亡激动因子(BCL-2-associated agonist of cell death, BAD)、BCL-2相互作用杀伤蛋白(BCL-2 interacting killer, BIK)、佛波酯诱导蛋白1(phorbol-12-myristate-13-acetate-induced protein 1，PMAIP1基因产物常写为NOXA)、p53上调凋亡调控因子(P53 upregulated modulator of apoptosis, PUMA)、BCL-2修饰因子(BCL-2 modifying factor, BMF)和Harakiri BCL2相互作用蛋白(harakiri, BCL-2 interacting protein, HRK)]^[10]。BAK和BAX是线粒体外膜上最重要的促凋亡蛋白，寡聚化后直接在线粒体外膜形成膜孔，抗凋亡蛋白BCL-2与促凋亡蛋白BAX/BAK相互作用后阻止其寡聚化和膜孔形成，进而阻断细胞凋亡；仅含BH3结构域的促凋亡蛋白可以直接激活促凋亡蛋白BAX/BAK以促进膜孔形成和细胞凋亡，也可与抗凋亡蛋白BCL-2互作，破坏BCL-2和BAX/BAK的平衡，进而促进膜孔形成与细胞凋亡^[11]。因此，BCL-2家族蛋白如同“三元开关”调控线粒体凋亡通路。BH结构域基序在进化上高度保守，BCL-2蛋白不仅存在于哺乳动物中，还广泛存在于多细胞动物和一些病毒中^[12]。

1.2 外源性凋亡通路

外源性细胞凋亡通路主要由细胞外配体结合细胞表面的死亡受体触发，这些死亡受体在胞内区域都具有一个蛋白互作结构域，称为死亡结构域(death domain, DD)，例如凋亡相关因子(factor-related apoptosis, Fas)、肿瘤坏死因子受体1 (tumor necrosis factor receptor 1, TNFR1)、肿瘤坏死因子相关凋亡诱导配体受体1/死亡受体4 (TNF-related apoptosis-inducing ligand receptor 1/ death receptor 4, TRAIL-R1/DR4)和肿瘤坏死因子相关凋亡诱导配体受体2/死亡受体5 (TNF-related apoptosis-inducing ligand receptor 2/death receptor 5, TRAIL-R2/DR5)，它们由相应的胞外配体激活^[1]。例如，Fas配体(Fas-ligand, FASL)或肿瘤坏死因子(tumor necrosis factor, TNF)-α与其细胞表面相对应的死亡受体Fas或TNF受体(TNF receptor, TNFR)结合，激活其死亡结构域并募集胞内TNF受体相关因子2 (TNF receptor-associated factor 2, TRAF2)、受体相互作用蛋白1 (receptor-interacting protein kinase 1, RIPK1)、细胞内凋亡抑制蛋白(cellular inhibitor of apoptosis protein, cIAP)、TNFR相关死亡结构域蛋白(TNFR-associated death domain protein, TRADD)，组装形成初级死亡信号复合体，而后进一步招募Fas相关死亡结构域蛋白(Fas-associated death domain protein, FADD)、Caspase 8、TRADD和RIPK1等蛋白，通过与FADD相互作用激活Caspase 8，活化的Caspase 8直接激活下游效应Caspase 3和Caspase 7，最终引发细胞凋亡^[13]。同时，在某些细胞中Caspase 8可以裂解并活化线粒体中仅有BH3结构域的蛋白BID，进而激活BAX和BAK，导致线粒体细胞凋亡^[8]。当Caspase 8活性被抑制时，活化的RIPK1与RIPK3结合并使其活化，进而RIPK3又磷酸化激活混合谱系激酶结构域样蛋白(mixed lineage kinase domain-like protein, MLKL)，通过破坏质膜的完整性来介导坏死性凋亡^[14]。

2 病原感染调控宿主细胞凋亡

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病原感染过程中宿主细胞凋亡在抵御病原体方面发挥着重要作用，这一过程受到宿主与病原体的双重调控。宿主细胞通过诱导凋亡来清除被感染的细胞，从而限制病原体的扩散并激活免疫反应^[15]。然而，病原体也进化出了多种策略来调控宿主细胞凋亡，其调控机制复杂且动态。某些病毒在感染前期抑制宿主细胞凋亡，而在后期通过诱导宿主细胞凋亡来释放子代病毒，进而快速感染邻近的健康细胞；而一些胞内寄生病原需要在宿主细胞内存活较长时间以完成其生命周期，这些病原体通过抑制宿主细胞凋亡来延长宿主细胞的存活时间，保证其在宿主细胞内的生存微环境^[16]。尽管宿主细胞凋亡通常对病原体有害，但部分病原体可利用细胞死亡途径进行播散。其调控机制的复杂性不仅源于细胞凋亡调控网络，还与感染剂量、宿主细胞类型、感染持续时间等变量相关。本文将重点综述胞内病原(病毒、细菌、真菌和寄生虫)对宿主细胞凋亡的调控策略(图1)。

2.1 病毒调控宿主细胞凋亡

病毒感染后的宿主细胞凋亡研究最为广泛。感染引起的宿主细胞凋亡对病毒复制具有双重作用。一方面，宿主细胞通过凋亡消除被病毒感染的细胞，进而消灭病毒；另一方面，病毒诱导宿主细胞凋亡作为释放和传播后代病毒的方式。在这2种情况下病毒都需要编码一些产物来阻止或延迟宿主细胞凋亡以实现病毒复制产生足够多的后代，一些病毒在复制时期会抑制宿主细胞凋亡，而在释放子代病毒时期会诱导细胞凋亡以增强传播^[17]。病毒调控宿主细胞凋亡的策略主要有2类：一是通过上游信号通路调控凋亡相关基因的表达；二是直接调控细胞凋亡通路中的关键环节，例如直接调控线粒体外膜通透性、死亡信号传导过程及Caspase蛋白酶活性。

病毒感染后可通过调控凋亡相关基因表达进而调控宿主细胞凋亡。日本脑炎病毒(Japanese encephalitis virus, JEV)感染导致DNA损伤，从而促进P53在细胞核中的磷酸化，并诱导BAX等促凋亡基因表达，进而影响宿主细胞凋亡^[18]。鸭坦布苏病毒(duck Tembusu virus, DTMUV)感染鸭胚成纤维细胞后，激活Caspase 8介导的死亡受体凋亡通路和Caspase 9介导的线粒体凋亡通路，诱导鸭胚成纤维细胞凋亡^[19-20]。人类免疫缺陷病毒HIV会通过调控死亡受体介导的细胞凋亡促进病毒感染，使宿主CD4⁺和CD8⁺ T细胞Fas、DR4和DR5表达增加，导致这些细胞对死亡受体介导的细胞凋亡敏感，进而引起T细胞耗竭，同时HIV感染还上调巨噬细胞中FasL的表达，进一步加剧T细胞凋亡，以此来削弱宿主免疫^[21-22]。

病毒编码模仿宿主抗凋亡BCL-2 (vBCL-2)蛋白，抑制线粒体细胞色素C的释放，劫持内源性凋亡通路^[23]。例如，腺病毒、小鼠γ-疱疹病毒、EB病毒和人疱疹病毒等产生哺乳动物BCL-2蛋白类似物可抑制BAX和BAK活性，进而抑制宿主细胞凋亡^[17]。相比之下，大多数痘病毒(Poxvirus)缺乏BCL-2同系物，但在黏液瘤病毒(Myxoma)中发现了一个凋亡抑制蛋白M11L，该蛋白结构与BCL-2类似，但序列相似性较低，以此为基础从痘病毒中鉴定出6个BCL-2结构类似蛋白，如羊痘病毒(sheep Poxvirus)编码的SPPV14蛋白可直接作用于BAX和BAK，抑制宿主细胞凋亡^[24]。

病毒编码蛋白能激活或抑制死亡受体介导的凋亡信号传导。死亡受体诱导的细胞凋亡过程：配体与受体结合后，衔接蛋白FADD通过死亡结构域组装成高阶死亡诱导信号复合体(death inducing signaling complex, DISC)，招募并激活Caspase 8，进而激活下游执行Caspase，最终引发凋亡^[1,13]。HIV编码的包膜糖蛋白GP120/GP41与受感染和未感染的CD4⁺ T细胞的凋亡过程相关，其中GP120可与CD4受体和趋化因子共受体(C-C motif chemokine receptor type 5, CCR5和C-X-C chemokine receptor type 4, CXCR4)结合并交联，GP120对CD4⁺ T细胞的交联诱导Fas介导的细胞凋亡敏感性增强^[25-26]。病毒编码的vFLIP (Fas-associated death domain-like interleukin-1β-converting enzyme inhibitory protein)含有与Caspase 8相同的死亡效应结构域，可竞争性结合FADD，进而阻止FADD-Caspase 8复合体组装，导致Caspase 8不能被激活，从而抑制细胞凋亡的发生^[27]。除此之外，人乳头瘤病毒16型(human papillomavirus-16, HPV-16)的E6蛋白虽并非vFLIP类蛋白，但也可靶向DISC的组装，从而抑制死亡受体诱导的凋亡，E6不仅可结合TNFR1的死亡结构域DD，阻止TNF受体相关死亡结构域蛋白TRADD招募，从而阻止DISC的形成；还可结合FADD和Caspase 8的死亡效应结构域，发挥与vFLIP类似作用阻断细胞凋亡^[28-29]。

病毒编码蛋白直接抑制Caspase家族蛋白酶活性调控宿主细胞凋亡。病毒编码3类抑制蛋白来拮抗半胱天冬酶活性，从而抑制宿主细胞凋亡。这些抑制蛋白包括丝氨酸蛋白酶抑制剂(serine protease inhibitor, Serpin)、p35家族成员、细胞凋亡抑制蛋白(viral inhibitor of apoptosis proteins, vIAP)^[30]。第一个被发现的病毒Caspase抑制剂是牛痘病毒(Cowpox virus)编码的细胞因子反应修饰剂A (cytokine response modifier A, CrmA)，其属于Serpin超家族^[31]。它最初被确定为白细胞介素(interleukin, IL)-1β转化酶(IL-1β-ICE)的抑制剂，后发现CrmA能抑制多种Caspase活性并防止宿主细胞凋亡和炎症^[32]。P35是从苜蓿银纹夜蛾核型多角体病毒(Autographa californica Nucleopolyhedrovirus, AcMNPV)中鉴定出的广谱Caspase抑制剂，可抑制病毒感染的昆虫细胞凋亡，也可抑制线虫CED-3、果蝇效应半胱天冬酶DrICE、哺乳动物Caspase 1、Caspase 3、Caspase 6等的活性^[33-34]。在杆状病毒中寻找可弥补p35缺失后抑制宿主细胞凋亡的效应因子时鉴定到细胞凋亡抑制蛋白IAP^[35]。除了杆状病毒外，IAP同系物还在昆虫痘病毒(Entomopoxvirus)、非洲猪瘟病毒(African swine fever virus)以及从酵母到人类的多种生物中被鉴定，在抑制Caspase活性及细胞凋亡中起重要作用^[36]。病毒调控宿主细胞凋亡的效应分子及信号通路见表1。

2.2 胞内病原细菌调控宿主细胞凋亡

细菌病原体通常通过分泌效应蛋白调控宿主信号通路，进而干预凋亡过程。尽管不同病原体在不同宿主细胞中调控凋亡的机制差异显著，但其调控策略仍存在一些共性，包括病原细菌分泌效应蛋白调控细胞凋亡上游信号通路(如PI3K/Akt等)、内源和外源凋亡通路关键蛋白以及凋亡通路下游关键蛋白酶等。

宿主细胞感知病原入侵后能通过P53、PI3K/Akt、核因子κB (nuclear factor kappa-B, NF-κB)等信号通路调控细胞凋亡或凋亡相关基因的转录，胞内病原细菌分泌系统通过分泌效应蛋白干扰这些细胞信号通路，从而调控宿主细胞凋亡^[65]。例如，弗氏志贺氏菌(Shigella flexneri)感染上皮细胞后P53细胞凋亡通路被激活，试图清除病原体，弗氏志贺氏菌通过Ⅲ型分泌系统(type Ⅲ secretion system, T3SS)分泌效应蛋白VirA，靶向降解钙蛋白酶抑制剂，解除其对P53的保护作用，进而促进P53降解，抑制宿主细胞凋亡^[66-67]。弗氏志贺氏菌还分泌一种磷脂酰肌醇磷酸酶IpgD，将磷脂酰肌醇- 4,5-二磷酸(phosphatidylinositol 4,5-bisphosphate, PIP2)转换成磷脂酰肌醇-5-磷酸(phosphatidylinositol 5-phosphate, PI5P)，进而促进表皮生长因子受体(epidermal growth factor receptor, EGFR)信号通路以维持PI3K/Akt激活，从而防止细胞凋亡^[68]。假结核耶尔森氏菌(Yersinia pseudotuberculosis)通过六型分泌系统(type VI secretion system, T6SS)分泌脱氧核糖核酸酶效应蛋白TkeA，并转运至宿主细胞内诱导DNA损伤，进而激活cGAS-STING-TNF轴诱导宿主细胞凋亡^[69]。肠沙门氏菌(Salmonella enterica)感染肠道上皮细胞时，通过T3SS分泌效应蛋白SopB介导PI3K/Akt通路激活，导致Akt磷酸化并影响细胞色素C的释放，抑制宿主细胞凋亡^[70-71]；沙门氏菌还可以在巨噬细胞中复制，并分泌效应蛋白SipB和SipD诱导巨噬细胞凋亡，从而减少炎症细胞因子的释放^[72]。同种病原对不同宿主细胞的凋亡调控策略不同：在用于增殖的宿主细胞中抑制凋亡，而在免疫防御细胞中诱导凋亡以规避宿主免疫应答。除此之外，嗜肺军团菌(Legionella pneumophila)分泌蛋白LegK1和LnaB^[73-74]，假结核耶尔森氏菌分泌蛋白YopJ^[75]，副溶血弧菌(Vibrio parahaemolyticus)分泌蛋白VopA^[76]，伯氏考克斯氏体(Coxiella burnetii)分泌蛋白AnkG等效应因子^[77]，这些效应蛋白均可靶向宿主细胞NF-κB等信号通路，调控凋亡相关基因表达，从而干预宿主细胞凋亡。

一些胞内病原细菌通过分泌效应蛋白调控宿主BCL-2家族蛋白的表达、激活、降解及功能等多个方面进而调控宿主细胞凋亡。结核分枝杆菌(Mycobacterium tuberculosis)能够侵染巨噬细胞并在其胞内复制，其分泌的MPT64蛋白下调宿主miR-21的表达后增加抗凋亡蛋白BCL-2的表达，进而抑制宿主细胞凋亡^[78]。此外，结核分枝杆菌分泌蛋白Rv0355c模拟真核生物的BCL-2蛋白，靶向宿主细胞线粒体，进而抑制宿主细胞凋亡^[79]。沙眼衣原体(Chlamydia trachomatis)感染具有很强的抗宿主细胞凋亡能力，感染后宿主细胞线粒体中细胞色素C释放受阻、Bax和Bak激活受抑制，研究发现其分泌的蛋白酶CPAF能够降解仅含BH3结构域的促凋亡BCL-2家族成员，增强了衣原体的抗凋亡活性^[80]，并且沙眼衣原体外膜蛋白OmpA通过外膜囊泡运输到宿主线粒体膜上，可以干扰促凋亡蛋白Bax的激活^[81]。同样地，脑膜炎奈瑟氏球菌(Neisseria meningitidis)分泌蛋白PorB也通过外膜囊泡运输到宿主细胞的线粒体外膜上，导致线粒体膜电位丧失、细胞色素C释放等促进宿主巨噬细胞凋亡，抑制宿主先天免疫反应^[82]。新兴病原体嗜包涵体无形体(Anaplasma phagocytophilum)分泌的Ats-1蛋白，其蛋白N端能够靶向并插入线粒体后被宿主线粒体肽酶切割，切割产物在线粒体外膜堆积，阻断Bax插入和膜孔形成，进而抑制线粒体膜通透性改变、细胞色素C释放和细胞凋亡^[83]。综上所述，一些胞内病原细菌调控宿主细胞凋亡的具体机制虽有差异，但都可以靶向细胞凋亡通路中关键的BCL-2蛋白家族策略来调控宿主细胞凋亡。

Caspase蛋白酶是细胞凋亡通路中下游的信号传导与执行分子，在细胞凋亡中起关键作用，一旦效应Caspase被激活细胞凋亡进程不能逆转，仅能被延迟。在长期的进化过程中，一些胞内细菌病原体为了适应宿主环境也演变出了一些策略调控Caspase活性^[84]。例如，包括弗氏志贺氏菌在内的革兰氏阴性菌，其脂多糖的O抗原部分能够直接与效应Caspase结合，通过抑制其活性有效延长宿主细胞的存活时间，为细菌自身的生存和繁殖争取更多时间和空间^[85]。嗜肺军团菌分泌类似真核生物的Ser/Thr激酶LegK3，可使效应Caspase 3、Caspase 7和Caspase 9的关键Ser/Thr位点发生磷酸化，这些修饰干扰执行Caspase作为上游起始Caspase底物的功能，进而影响细胞凋亡的进程，但不影响执行Caspase的水解活性^[86]。为了在宿主细胞内更好地存活，细菌通过分泌效应蛋白采取多种策略调控宿主细胞凋亡，包括干预信号通路、调控凋亡相关基因表达，以及影响凋亡通路中关键蛋白及蛋白酶活性等。不同病原的策略并不完全相同，随着对细胞凋亡、病原与宿主互作机制的研究越来越深入，越来越多病原调控宿主细胞凋亡的未解之谜将慢慢揭开。部分胞内寄生菌调控宿主细胞凋亡的效应分子及介导的通路见表2。

2.3 其他胞内寄生病原调控宿主细胞凋亡

除了病毒和细菌外，一些真菌及原生动物等胞内寄生病原也会调控宿主细胞凋亡。例如，微孢子虫(Microsporidia)是一类专性胞内寄生的真菌病原，广泛分布于自然界中，目前鉴定的微孢子虫超过1 800种^[100]。微孢子虫早期被认为是原虫，后被归类为与真菌亲缘关系密切的姊妹群^[101]。微孢子虫营细胞内专性寄生，高度依赖宿主细胞存活。研究发现兔脑炎微孢子虫、蜜蜂微孢子虫和家蚕微粒子虫等感染相应宿主细胞后均出现抑制宿主细胞凋亡的现象，涉及阻止凋亡因子P53入核、抑制宿主细胞内活性氧生成及调控凋亡相关基因转录等^[102-105]。最新研究发现，家蚕微粒子虫中存在serpin蛋白家族成员NbSPN14，该蛋白被分泌到宿主细胞中，与宿主家蚕细胞凋亡通路关键效应Caspase酶BmICE相互作用并抑制其活性，进而抑制宿主细胞凋亡，首次鉴定了微孢子虫中抑制宿主细胞凋亡的效应分子^[106-108]。

顶复门原虫是一类专性细胞内寄生原虫，包含弓形虫、疟原虫、隐孢子虫、球虫等多种病原体，感染后抑制宿主细胞凋亡，为自身生长、繁殖创造有利条件^[109]。顶复门原虫通过3种方式抑制细胞凋亡。(1) 分泌微线体蛋白(microneme proteins, MICs)，这些蛋白在寄生虫侵入宿主细胞和抑制凋亡中起重要作用。例如，鸡球虫的MIC4蛋白通过与表皮生长因子受体(EGFR)相互作用激活EGFR/Akt信号通路，从而抑制宿主细胞凋亡^[110]。同样地，弓形虫的MIC3、MIC6和MIC8蛋白借助其含有的EGF结构域激活EGFR/Akt信号通路，抑制宿主细胞凋亡^[111-112]。(2) 分泌棒状体蛋白(rhoptry proteins, ROPs)，弓形虫分泌ROP16蛋白激活STAT3和STAT6信号通路，抑制宿主细胞凋亡^[113-114]。ROP18蛋白通过磷酸化P65促进其降解，抑制NF-κB激活，从而抑制宿主细胞凋亡^[115]。(3) 分泌致密颗粒蛋白(dense granule proteins, GRAs)来抑制宿主细胞凋亡，例如弓形虫分泌GRA24蛋白通过激活p38 MAPK，诱导GPCR/PI3K/Akt信号通路抑制宿主细胞凋亡^[116]。此外，热激蛋白(heat shock proteins, HSPs)在顶复门原虫中也发挥重要作用，弓形虫的HSP70蛋白通过抑制细胞色素C的释放、促进抗凋亡蛋白表达和抑制Caspase活性从而抑制宿主细胞凋亡^[117]。这些寄生虫通过劫持NF-κB、PI3K-Akt和线粒体凋亡通路等机制共同作用，使得顶复门原虫能够在感染后抑制宿主细胞凋亡，为其自身的生长、发育和繁殖创造有利条件。

3 总结与展望

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宿主与病原体的相互作用作为生物进化的主要驱动力，引发了二者在防御与逃避策略上的“军备竞赛”。多细胞生物中调节性细胞死亡作为古老的免疫防御机制，其激活和执行机制十分复杂且受到严格调控，在限制病原体传播和保护自身存活中发挥重要作用；而病原体也发展出多种策略逃避或干扰调节性细胞死亡的信号传导^[118]。本文综述了胞内寄生病原调控宿主细胞凋亡的机制与策略，总结了胞内寄生病原通过调控细胞凋亡上游信号通路来调控凋亡相关基因表达，产生效应分子直接调控细胞凋亡通路信号传导和执行过程，如调节BCL-2家族蛋白影响线粒体外膜通透性、调控死亡信号受体与配体结合及Caspase 8活性、直接调控凋亡执行分子效应Caspase活性等策略调控宿主细胞凋亡。细胞凋亡是第一个被确定的调节性细胞死亡形式，其调控机制研究已十分深入和清晰^[5]，但细胞凋亡在对抗病原感染方面的具体效果如何，诸多胞内寄生病原抑制或诱导细胞凋亡的分子机制尚不完全清楚，胞内寄生病原感染与细胞凋亡及其他调节性细胞死亡交叉调控关系等问题有待深入探究。胞内寄生病原侵入宿主细胞后依赖并利用宿主细胞资源进行复制和传播，因此需要保证宿主细胞存活以完成其增殖，但最终都会导致宿主细胞死亡。未来的研究应聚焦于深入解析病原体产生的效应分子操纵宿主细胞死亡的分子机制，这将有助于揭示病原与宿主相互作用的奥秘，为开发新的抗感染策略和治疗手段提供理论依据。

作者贡献声明

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冉茂双：数据收集和处理及文章撰写；包佳玲：修订审阅；潘国庆：论文构思和审阅，项目管理。

作者利益冲突公开声明

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作者声明不存在任何可能会影响本文所报告工作的已知经济利益或个人关系。

基金

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国家自然科学基金(32272942)
国家自然科学基金(32272944)
重庆市现代农业产业技术体系(COMAITS202311)
中央高校基本科研业务费专项资金(SWU-XDJH202322)
重庆市博士后特别资助项目(2023CQBSHTB3030)

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2025年第65卷第11期

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doi: 10.13343/j.cnki.wsxb.20250357

接收时间：2025-04-29
首发时间：2025-11-10
出版时间：2025-11-04

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出版历史

收稿日期：2025-04-29
录用日期：2025-07-09

基金

National Natural Science Foundation of China(32272942)

国家自然科学基金(32272942)

National Natural Science Foundation of China(32272944)

国家自然科学基金(32272944)

Chongqing Modern Agricultural Industry Technology System(COMAITS202311)

重庆市现代农业产业技术体系(COMAITS202311)

Fundamental Research Funds for the Central Universities(SWU-XDJH202322)

中央高校基本科研业务费专项资金(SWU-XDJH202322)

Special Funding for Chongqing Postdoctoral Research Project(2023CQBSHTB3030)

重庆市博士后特别资助项目(2023CQBSHTB3030)

作者信息

1 西南大学，资源昆虫高效养殖与利用全国重点实验室，重庆

2 西南大学，微孢子虫感染与防控重庆市重点实验室，重庆

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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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Virus	Classification	Viral effector	Mediated signaling	References
African swine fever virus (ASFV)	Viral pro survival BCL-2 proteins	A179L	MOMP	[37]
Pseudorabies virus	gM	MOMP	[38]
γ-herpesviruses 68	M11	MOMP	[39-40]
Adenovirus	E1B19K	MOMP	[41]
Epstein-Barr virus	BHRF1	MOMP	[42-43]
Kaposi’s sarcoma-associated herpesvirus	Ks-Bcl-2	MOMP	[44]
Türkiye herpesvirus	vNr-13	MOMP	[45]
Orfvirus	ORFV125	MOMP	[46]
Hepatitis B virus	HBx	MOMP	[47]
Grouper iridovirus	GIV66	MOMP	[48]
Myxoma virus	M11L	MOMP	[49]
Vaccinia virus	F1L	MOMP	[50]
Ectromelia virus	EMV025	MOMP	[51]
Sheeppox virus	SPPV14	MOMP	[52]
Deerpox virus	DPV022	MOMP	[53]
Fowlpox virus	FPV029	MOMP	[54]
Canarypox	CNP058	MOMP	[55]
Tanapoxvirus	TANV16L	MOMP	[56]
HIV-1	Death receptor activator	Tat/Env/Vpu/gp120	Fas, TNF-R	[21,57]
HCV	Core protein	Fas, TNF-R	[58]
Epstein-Barr virus	LMP2A/LMP1	Fas	[59-60]
Lyssavirus	Matrix protein	TRAIL-R	[61]
γ-herpesviruses	Death receptor inhibitor	vFLIP	DISC	[62]
Molluscum contagiosum virus	MC159	DISC	[63]
HPV	E6	DISC	[28]
Poxvirus	Caspase inhibitor	Serpin	Caspase	[64]
Baculovirus	P35	Caspase	[34]
Virus	IAP	Caspase	[36]

Virus

Classification

Viral effector

Mediated signaling

References

African swine fever virus (ASFV)

Viral pro survival BCL-2 proteins

A179L

MOMP

[37]

Pseudorabies virus

MOMP

[38]

γ-herpesviruses 68

M11

MOMP

[39-40]

Adenovirus

E1B19K

MOMP

[41]

Epstein-Barr virus

BHRF1

MOMP

[42-43]

Kaposi’s sarcoma-associated herpesvirus

Ks-Bcl-2

MOMP

[44]

Türkiye herpesvirus

vNr-13

MOMP

[45]

Orfvirus

ORFV125

MOMP

[46]

Hepatitis B virus

HBx

MOMP

[47]

Grouper iridovirus

GIV66

MOMP

[48]

Myxoma virus

M11L

MOMP

[49]

Vaccinia virus

F1L

MOMP

[50]

Ectromelia virus

EMV025

MOMP

[51]

Sheeppox virus

SPPV14

MOMP

[52]

Deerpox virus

DPV022

MOMP

[53]

Fowlpox virus

FPV029

MOMP

[54]

Canarypox

CNP058

MOMP

[55]

Tanapoxvirus

TANV16L

MOMP

[56]

HIV-1

Death receptor activator

Tat/Env/Vpu/gp120

Fas, TNF-R

[21,57]

HCV

Core protein

Fas, TNF-R

[58]

Epstein-Barr virus

LMP2A/LMP1

Fas

[59-60]

Lyssavirus

Matrix protein

TRAIL-R

[61]

γ-herpesviruses

Death receptor inhibitor

vFLIP

DISC

[62]

Molluscum contagiosum virus

MC159

DISC

[63]

HPV

DISC

[28]

Poxvirus

Caspase inhibitor

Serpin

Caspase

[64]

Baculovirus

P35

Caspase

[34]

Virus

IAP

Caspase

[36]

Bacterium	Effector	Targeted pathway	Mediated signaling	References
Shigella flexneri	VirA	P53	P53	[66-67]
IpgD	PI3K/Akt	PI3K/Akt	[87-88]
OspZ	TAB2/3, IkB	NF-κB, transcription	[89]
Salmonella enterica	SopB/SigD	PDK1/Rictor	PI3K/Akt	[70,90]
SseK1, SseK 2, SseK 3	TRADD	NF-κB	[91-92]
Legionella pneumophila	LegK1, LnaB	IκBα	NF-κB	[74,93]
SidF	BCL-2	MOMP	[94]
LegK3	Caspase 3, Caspase 7, Caspase 9	Caspase	[86]
LPS O-antigen	Caspase	Caspase	[85]
Chlamydia trachomatis	CPAF	BH-3 only	MOMP	[75]
OmpA	Bax/Bak	MOMP	[81]
CT622	Unknow	MAPK	[95]
Yersinia pseudotuberculosis	YopJ	ERK/p38/JNK	NF-κB, MAPK	[75]
YopK	Unknow	Extrinsic	[96]
Vibrio parahaemolyticus	VopA	MAPKKs	MAPK	[76]
Coxiella burnetii	AnkG	P32	Intrinsic	[77,97]
CaeA	Unknown	Intrinsic/extrinsic	[98]
Mycobacterium tuberculosis	MPT64	BCL-2	MOMP	[73]
Rv0355c	BAK	MOMP	[79]
Rv2387	Caspase 3, Caspase 8	Caspase	[99]
ESAT-6	Caspase 3, Caspase 8	ROS/MAPK-Caspase	[99]
Neisseria meningitidis	PorB	BCL-2	MOMP	[82]

Bacterium

Effector

Targeted pathway

Mediated signaling

References

Shigella flexneri

VirA

P53

[66-67]

IpgD

PI3K/Akt

[87-88]