微生物学报

Classification	Name	In vivo/In vitro	Pathway or mechanism of action	References
Polysaccharide	Platycodon grandiflorus polysaccharide	In vitro	Inhibit the replication of PRV Reduce mitochondrial damage and the levels of mitochondrial pathway-induced apoptosis Downregulate PRV-induced autophagy via the Akt/mTOR pathway	[34-35]
Hippophae rhamnoides polysaccharide	In vitro	Inhibit the adsorption and entry of PRV Reduce PRV infection-induced oxidative stress	[36]
Panax notoginseng polysaccharide	In vitro	Inhibit the adsorption and replication of PRV	[37-38]
Glycyrrhiza polysaccharide	In vitro	Inhibit the adsorption and internalization of PRV	[39-43]
Isatis root polysaccharide	In vitro	Inhibit the replication of PRV Stimulate the maturation of DCs, induce IL-12 and IL-6 secretion	[44-46]
Huaier polysaccharide	In vitro	Inhibit the adsorption and entry of PRV	[47-48]
Flavonoid	Luteolin	Mice	Diminish the proinflammatory mediators NO, inflammatory cytokines and the expression of their regulatory genes, iNOS and COX-2 Inhibit STAT1/3 dependent NF-κB activation and induce Nrf2 mediated HO-1 expression	[49-50]
Flos Lonicerae Japonicae water extract	In vitro	Reduce the expression of proinflammatory mediators and inflammatory cytokines, such as COX-2 and iNOS, through the suppression of the JAK/STAT1/3-dependent NF-κB pathway and the induction of HO-1 expression	[51]
Myricetin	Mice	Directly inactivate virus Inhibit the adsorption and entry of PRV Activate the cGAS/STING pathway Regulate NF-κB/MAPK pathway, inflammatory response and apoptosis	[52-53]
Ethyl acetate fraction of flavonoids from Polygonum hydropiper L	Mice	Inhibit NO synthesis and downregulate the expression and secretion of COX-2, iNOS and inflammatory cytokines Reduce translocation of NF-κB p65 to the nucleus and MAPK phosphorylation Regulate Nrf2 signaling pathway and histone acetylation, and alleviate oxidative stress induced by PRV-infected mice	[54-55]
Dihydromyricetin	In vitro	Directly inactive virus Inhibit the adsorption and replication of PRV Activate NF-κB pathway and downregulate expression levels of inflammatory genes TNF-α, IL-1α, and IL-6 via the NF-κB pathway Inhibit the release of Bax and cytochrome c and exert anti-apoptotic effects	[56]
Kaempferol	Mice	Inhibit the IE180 transcription Inhibit transcription levels of LAT	[57]
Quercetin	Mice	Inhibit PRV adsorption by blocking the binding of nectin-1 to gD Reduce ROS secretion and alleviate oxidative stress caused by PRV infection	[58]
Isobavachalcone	In vitro	Impair virus-induced cell-to-cell fusion	[59]
Phenols	Curcumin	Mice	Inhibit the reduction of BDNF to protect neurons Improve mitochondrial function and AMPK/NF-κB p65 energy metabolism	[60-62]
Oregano essential oil	In vitro	Directly kill virus at high concentration Up-regulate the expression of TNF-α, IFN-β, IFN-γ, and IL-12	[63]
Resveratrol	Mice, piglets	Inhibit the IE180 transcription Increase the protein levels of TLR4, Ikk, IκBα, NF-κB, JNK and inhibit the degradation of IκB kinase	[64-67]
Alkaloid	β-carboline derivative	In vitro	Inhibit the macropinocytosis-dependent entry of PRV into cells by inhibiting DYRK1A	[68]
(S)-10-hydroxycamptothecin	Mice	Inhibit PRV replication by blocking PRV genome replication and targeting DNA topoisomerase 1 (TOP1) Induce DNA damage response, stimulate antiviral innate immunity and enhance INF-β response.	[69]
Monocyclic sesquiterpenoids	Germacrone	In vitro	Inhibit the replication of PRV	[70]
Natural anthraquinone derivative	Emodin	Mice	Inhibit the replication of PRV Inhibit the expression of PRV gene and the protein expression of PRV gB and gD Inhibit the PRV-induced apoptosis	[71]
Acid	Ginkgolic acid	Mice	Inhibit the late gene transcription of PRV	[72]
Steroid	Bufalin	Mice	Inhibit the entry of PRV	[73]
Stilbene-like compound	Piceatannol	Mice	Reduce the transcription levels of PRV genes Reduce PRV-induced apoptosis Increase the expression of IL-4, TNF-α, and IFN-γ	[74]
Ester	Gallocatechin gallate	Mice	Inhibit the entry and release of PRV	[75-76]
Extract	Dandelion aqueous extract	Mice	Inhibit the adsorption and replication of PRV Decrease the expression of PRV gene Regulate the production of cytokines	[77]
Natto extract	Mice	Inactivate PRV via proteolysis	[78]

Classification	Name	In vivo/In vitro	Pathway or mechanism of action	References
Polysaccharide	Platycodon grandiflorus polysaccharide	In vitro	Inhibit the replication of PRV Reduce mitochondrial damage and the levels of mitochondrial pathway-induced apoptosis Downregulate PRV-induced autophagy via the Akt/mTOR pathway	[34-35]
Hippophae rhamnoides polysaccharide	In vitro	Inhibit the adsorption and entry of PRV Reduce PRV infection-induced oxidative stress	[36]
Panax notoginseng polysaccharide	In vitro	Inhibit the adsorption and replication of PRV	[37-38]
Glycyrrhiza polysaccharide	In vitro	Inhibit the adsorption and internalization of PRV	[39-43]
Isatis root polysaccharide	In vitro	Inhibit the replication of PRV Stimulate the maturation of DCs, induce IL-12 and IL-6 secretion	[44-46]
Huaier polysaccharide	In vitro	Inhibit the adsorption and entry of PRV	[47-48]
Flavonoid	Luteolin	Mice	Diminish the proinflammatory mediators NO, inflammatory cytokines and the expression of their regulatory genes, iNOS and COX-2 Inhibit STAT1/3 dependent NF-κB activation and induce Nrf2 mediated HO-1 expression	[49-50]
Flos Lonicerae Japonicae water extract	In vitro	Reduce the expression of proinflammatory mediators and inflammatory cytokines, such as COX-2 and iNOS, through the suppression of the JAK/STAT1/3-dependent NF-κB pathway and the induction of HO-1 expression	[51]
Myricetin	Mice	Directly inactivate virus Inhibit the adsorption and entry of PRV Activate the cGAS/STING pathway Regulate NF-κB/MAPK pathway, inflammatory response and apoptosis	[52-53]
Ethyl acetate fraction of flavonoids from Polygonum hydropiper L	Mice	Inhibit NO synthesis and downregulate the expression and secretion of COX-2, iNOS and inflammatory cytokines Reduce translocation of NF-κB p65 to the nucleus and MAPK phosphorylation Regulate Nrf2 signaling pathway and histone acetylation, and alleviate oxidative stress induced by PRV-infected mice	[54-55]
Dihydromyricetin	In vitro	Directly inactive virus Inhibit the adsorption and replication of PRV Activate NF-κB pathway and downregulate expression levels of inflammatory genes TNF-α, IL-1α, and IL-6 via the NF-κB pathway Inhibit the release of Bax and cytochrome c and exert anti-apoptotic effects	[56]
Kaempferol	Mice	Inhibit the IE180 transcription Inhibit transcription levels of LAT	[57]
Quercetin	Mice	Inhibit PRV adsorption by blocking the binding of nectin-1 to gD Reduce ROS secretion and alleviate oxidative stress caused by PRV infection	[58]
Isobavachalcone	In vitro	Impair virus-induced cell-to-cell fusion	[59]
Phenols	Curcumin	Mice	Inhibit the reduction of BDNF to protect neurons Improve mitochondrial function and AMPK/NF-κB p65 energy metabolism	[60-62]
Oregano essential oil	In vitro	Directly kill virus at high concentration Up-regulate the expression of TNF-α, IFN-β, IFN-γ, and IL-12	[63]
Resveratrol	Mice, piglets	Inhibit the IE180 transcription Increase the protein levels of TLR4, Ikk, IκBα, NF-κB, JNK and inhibit the degradation of IκB kinase	[64-67]
Alkaloid	β-carboline derivative	In vitro	Inhibit the macropinocytosis-dependent entry of PRV into cells by inhibiting DYRK1A	[68]
(S)-10-hydroxycamptothecin	Mice	Inhibit PRV replication by blocking PRV genome replication and targeting DNA topoisomerase 1 (TOP1) Induce DNA damage response, stimulate antiviral innate immunity and enhance INF-β response.	[69]
Monocyclic sesquiterpenoids	Germacrone	In vitro	Inhibit the replication of PRV	[70]
Natural anthraquinone derivative	Emodin	Mice	Inhibit the replication of PRV Inhibit the expression of PRV gene and the protein expression of PRV gB and gD Inhibit the PRV-induced apoptosis	[71]
Acid	Ginkgolic acid	Mice	Inhibit the late gene transcription of PRV	[72]
Steroid	Bufalin	Mice	Inhibit the entry of PRV	[73]
Stilbene-like compound	Piceatannol	Mice	Reduce the transcription levels of PRV genes Reduce PRV-induced apoptosis Increase the expression of IL-4, TNF-α, and IFN-γ	[74]
Ester	Gallocatechin gallate	Mice	Inhibit the entry and release of PRV	[75-76]
Extract	Dandelion aqueous extract	Mice	Inhibit the adsorption and replication of PRV Decrease the expression of PRV gene Regulate the production of cytokines	[77]
Natto extract	Mice	Inactivate PRV via proteolysis	[78]

Classification	Name	In vivo/in vitro	Pathway or mechanism of action	References
IFN-Ⅰ and ISGs proteins	Porcine IFN-α-156s	Mice	Inhibit the replication of PRV	[82]
	Porcine IFNα+IL-2	Mice	Enhance the proliferation of peripheral blood mononuclear cells Increase the expression of ISGs, IFN-γ, IL-10, and inhibit the expression of IL-1β and IL-6	[83-84]
Swine NONO	In vitro	Enhance the activation of IFN-β promoter and IFN-β expression	[85]
Porcine IFN-δ8	In vitro	Increase the expression of ISGs Positively regulate the ISGs transcription levels	[86-87]
Mx protein	In vitro	Inhibit the synthesis of early genes UL54 and EP0 Inhibit PRV DNA transport to the nucleus	[88-89]
Porcine IFITM1	In vitro	Restrict PRV entry	[90-91]
Porcine ISG15	In vitro	Decrease the viral titer and mRNA levels of PRV Increase expression of IFN-β and activate interferon stimulated response element (ISRE) promoters	[92]
Host defense peptides	Cathelicidin-B1	Mice	Inhibit pseudorabies virus infection via direct interaction and TLR4/JNK/IRF3-mediated interferon activation	[93]
Piscidin1	Mice	Direct interact with viral particles to inhibit PRV Inhibit PRV-induced apoptosis	[94]
Porcineβ-defensin-2	Mice	Inhibit PRV proliferation in cells	[95]
AGDP	In vitro	Inhibit the expression of TNF-α and IL-8 Inhibit the degradation of IκBα and the phosphorylation level of p65 after PRV infection	[96]

Classification	Name	In vivo/in vitro	Pathway or mechanism of action	References
IFN-Ⅰ and ISGs proteins	Porcine IFN-α-156s	Mice	Inhibit the replication of PRV	[82]
	Porcine IFNα+IL-2	Mice	Enhance the proliferation of peripheral blood mononuclear cells Increase the expression of ISGs, IFN-γ, IL-10, and inhibit the expression of IL-1β and IL-6	[83-84]
Swine NONO	In vitro	Enhance the activation of IFN-β promoter and IFN-β expression	[85]
Porcine IFN-δ8	In vitro	Increase the expression of ISGs Positively regulate the ISGs transcription levels	[86-87]
Mx protein	In vitro	Inhibit the synthesis of early genes UL54 and EP0 Inhibit PRV DNA transport to the nucleus	[88-89]
Porcine IFITM1	In vitro	Restrict PRV entry	[90-91]
Porcine ISG15	In vitro	Decrease the viral titer and mRNA levels of PRV Increase expression of IFN-β and activate interferon stimulated response element (ISRE) promoters	[92]
Host defense peptides	Cathelicidin-B1	Mice	Inhibit pseudorabies virus infection via direct interaction and TLR4/JNK/IRF3-mediated interferon activation	[93]
Piscidin1	Mice	Direct interact with viral particles to inhibit PRV Inhibit PRV-induced apoptosis	[94]
Porcineβ-defensin-2	Mice	Inhibit PRV proliferation in cells	[95]
AGDP	In vitro	Inhibit the expression of TNF-α and IL-8 Inhibit the degradation of IκBα and the phosphorylation level of p65 after PRV infection	[96]

Classification	Name	In vivo/In vitro	Pathway or mechanism of action	References
Mold metabolites	4 virantmycin	In vitro	Mechanism unknown	[105]
	T-2 toxin	In vitro	Inhibit the replication of PRV Inhibit oxidative stress and apoptosis signaling pathways	[106]
	Ivermectin	Mice	Interrupt the localization of PRV UL42 in the nucleus	[107]
	Napyradiomycin A4	In vitro	/	[108]
Bacterial metabolites	Secondary metabolites of Bacillus subtilis L2	Mice	Inhibit the adsorption, entry and replication of PRV	[109]
	Lactobacillus isolates	Mice	Inhibit PRV proliferation in cells	[110]
	Polycyclic meroterpenoids, talaromyolides E−K	In vitro	It has a dose-dependent inhibitory effect on PRV	[111]

Classification	Name	In vivo/In vitro	Pathway or mechanism of action	References
Mold metabolites	4 virantmycin	In vitro	Mechanism unknown	[105]
	T-2 toxin	In vitro	Inhibit the replication of PRV Inhibit oxidative stress and apoptosis signaling pathways	[106]
	Ivermectin	Mice	Interrupt the localization of PRV UL42 in the nucleus	[107]
	Napyradiomycin A4	In vitro	/	[108]
Bacterial metabolites	Secondary metabolites of Bacillus subtilis L2	Mice	Inhibit the adsorption, entry and replication of PRV	[109]
	Lactobacillus isolates	Mice	Inhibit PRV proliferation in cells	[110]
	Polycyclic meroterpenoids, talaromyolides E−K	In vitro	It has a dose-dependent inhibitory effect on PRV	[111]

天然生物活性分子抗伪狂犬病病毒感染的研究进展

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代宇 , 刘宜雨 , 叶超 ^*

微生物学报 | 综述 2024,64(10): 3591-3609

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微生物学报 | 综述 2024, 64(10): 3591-3609

天然生物活性分子抗伪狂犬病病毒感染的研究进展

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代宇, 刘宜雨, 叶超^*

作者信息

西南大学动物医学院, 动物健康与动物性食品安全国际合作联合实验室, 重庆 400715

Research progress on natural bioactive molecules against pseudorabies virus infection

Yu DAI, Yiyu LIU, Chao YE^*

Affiliations

Joint International Research Laboratory of Animal Health and Animal Food Safety, College of Veterinary Medicine, Southwest University, Chongqing 400715, China

出版时间: 2024-07-02 doi: 10.13343/j.cnki.wsxb.20240207

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摘要

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伪狂犬病病毒(pseudorabies virus, PRV)是疱疹病毒科水痘病毒属的成员，主要引起以母猪流产、仔猪神经和呼吸道症状为特征的伪狂犬病，对生猪养殖生产造成极大的威胁。疫苗免疫是预防猪伪狂犬病最重要的措施，但因病毒发生变异和具有潜伏感染特性，导致传统疫苗防治效果不佳。因此，临床上急需新的药物制剂辅助疫苗免疫来防治该病。研究发现，天然植物类多糖及黄酮、酚、酸等小分子物质能够通过直接抑制病毒感染过程或者通过调节免疫反应抑制PRV感染。另外，宿主抗病毒蛋白Ⅰ型干扰素及其下游干扰素刺激基因对PRV的感染也具有显著的抑制作用，抗菌肽和防御素等宿主防御肽对PRV的感染也有较好的抑制作用。另外，研究人员最近发现，细菌和真菌的提取物及其代谢产物也具有抗PRV的作用，未来有望将细菌和真菌及其产物应用于病毒病的防控和治疗。本文重点讨论了近年天然生物活性分子抗PRV感染的相关研究进展，以期为抗PRV感染药物的研发提供重要参考。

关键词

伪狂犬病病毒 / 植物源抗病毒分子 / 宿主防御肽 / Ⅰ型干扰素 / 干扰素刺激基因 / 细菌代谢物 / 真菌代谢物

Abstract

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Pseudorabies virus (PRV) is a member of the genus Varicellovirus in the Herpesviridae family. It primarily causes pseudorabies characterized by reproductive failure in sows, and neurological and respiratory symptoms in piglets, posing a significant threat to pig production. Vaccination is the most important measure to prevent PRV in pigs. However, due to variations of the virus and its latent infection characteristics, the effectiveness of traditional vaccines is compromised. Consequently, there is an urgent need for new drug preparations to assist vaccine immunization. It has been found that natural plant polysaccharides and small molecules such as flavonoids, phenols, and acids can inhibit PRV infection either by directly blocking the viral infection process or by regulating the immune response. In addition, host antiviral protein type Ⅰ interferon and its downstream interferon-stimulated genes have significant inhibitory effects on PRV infection. Host defense peptides, including antimicrobial peptides and defensins, also show good inhibitory effects on PRV infection. Interestingly, researchers have recently found that extracts and metabolites from bacteria and fungi also exhibit anti-PRV effects, and it is expected that these bacteria and fungi and their products could be applied for the prevention and treatment of viral diseases in the future. This study focused on the recent research progress of natural bioactive molecules against PRV infection, aiming to provide important references for the research and development of anti-PRV infection drugs.

Key words

pseudorabies virus / plant-derived antiviral molecules / host defense peptides / type Ⅰ interferon (IFN-I) / interferon-stimulated genes (ISGs) / bacterial metabolites / fungal metabolites

引用本文

代宇, 刘宜雨, 叶超. 天然生物活性分子抗伪狂犬病病毒感染的研究进展. 微生物学报, 2024 , 64 (10) : 3591 -3609 . DOI: 10.13343/j.cnki.wsxb.20240207

Yu DAI, Yiyu LIU, Chao YE. Research progress on natural bioactive molecules against pseudorabies virus infection[J]. Acta Microbiologica Sinica, 2024 , 64 (10) : 3591 -3609 . DOI: 10.13343/j.cnki.wsxb.20240207

正文

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伪狂犬病是由伪狂犬病病毒(pseudorabies virus, PRV)感染引起的一种主要危害猪群健康的传染病；仔猪感染死亡率较高，主要表现为神经症状和呼吸系统损伤，妊娠母猪感染以流产、产死胎、木乃伊胎为特征，公猪感染主要是睾丸损伤，影响种用价值^[1]。PRV属于疱疹病毒科α-疱疹病毒亚科水痘病毒属，为双链DNA病毒。PRV可以在猪的中枢神经系统中建立潜伏感染，PRV潜伏感染期间，猪无临床症状，但当受到应激源的刺激时，潜伏的病毒可以被重新激活，导致潜伏感染猪带毒排毒，对猪场伪狂犬病的防控造成极大的困扰^[2]。此外，国外早在20世纪80年代就有研究发现，PRV疑似可以感染人类^[3]。现有研究表明，PRV可以侵入人类中枢神经系统，导致感染病毒性脑炎，临床表现为发热、震颤、癫痫、视力障碍等，目前对于人感染PRV并无死亡病例，大量的抗病毒和抗炎药物可以进行对症治疗，但是目前无特效药物进行治疗且多预后不良^[4]。2020年，相关研究从1例急性人脑炎病例中分离出1株PRV毒株，该分离株与我国PRV变异株具有密切的系统发育关系和相似的病原学特征^[5-6]，提示着PRV对人类健康具有潜在威胁。虽然人感染PRV病例不多，主要是有动物暴露史或从事兽医相关工作的人员，而且尚未发现人与人之间传染的现象，但人感染PRV的病例提示伪狂犬病在公共卫生方面的重要性，其不仅造成畜牧生产上的损失，还可能危害人类健康^[7]。

猪伪狂犬病的预防主要是通过疫苗免疫，并且起到了较好预防效果，临床生产上常用Bartha K61活疫苗对经典PRV进行免疫防控。2011年以来，PRV出现变异毒株，传统的Bartha K61对某些变异毒株仍具有良好的免疫作用。例如，Papageorgiou等通过动物实验，确认Bartha-K61可以对中国PRV变异株HeN1株提供可靠保护^[8]。同时，Bartha-K61疫苗也可对另一PRV变异株vPRV/XJ5株的致死性、亚致死性攻毒提供与变异株疫苗同等保护^[9-11]。然而，研究发现Bartha K61活疫苗对某些流行变异株不能提供完全保护^[12]，在较多免疫传统疫苗的猪场出现免疫失败的现象^[13]。此外，近期研究发现，临床上出现了Bartha毒株和PRV变异株的天然重组株，提示当前所用疫苗对于PRV的防控效果仍稍显不足^[14]。目前，大量研究发现，多种天然来源的生物活性分子表现出较好的抗PRV感染作用。因此，通过从天然生物活性药物分子方面寻找新的猪伪狂犬病防控和治疗的契机将是一个具有前景的研究方向。

1 PRV感染宿主细胞的分子机制概述

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PRV感染宿主细胞后，主要通过其编码的糖蛋白C (glycoprotein C, gC)，糖蛋白D glycoprotein D, gD)、糖蛋白B (glycoprotein B, gB)、糖蛋白H (glycoprotein H, gH)、糖蛋白L(glycoprotein L, gL)等糖蛋白与细胞受体结合，介导病毒包膜和细胞质膜的融合从而进入细胞；然后通过一系列的信号级联反应完成复制、组装、释放过程，实现病毒增殖^[15]。PRV基因分为立即早期基因、早期基因和晚期基因，通过级联反应调控PRV复制。IE180是PRV中唯一的立即早期基因，也是PRV复制周期的起点，并且立即早期蛋白(immediate-early protein, IE180)是参与DNA复制和RNA转录的有效转录激活剂，缺乏IE180蛋白的病毒不能进行复制^[16]。

宿主可以通过模式识别受体(pattern recognition receptor, PRR)识别入侵病毒的成分来建立抗病毒状态，激活相关信号通路产生Ⅰ型干扰素(type Ⅰ interferon, IFN-I)、促炎因子和趋化因子等来抵抗PRV感染^[17]。PRV DNA首先被环磷酸鸟苷-腺苷合成酶(cyclic guanosine monophosphate-adenosine monophosphate synthase, cGAS)识别，进而催化第二信使环鸟苷酸-腺苷酸(cyclic guanosine monophosphate- adenosine monopho-sphate, cGAMP)的产生，cGAMP与位于内质网上的干扰素基因刺激因子(stimulator of interferon gene, STING)结合，易位到高尔基体以募集TANK结合激酶1 (TANK-binding kinase-1, TBK1)和干扰素调节转录因子3/7 (interferon regulatory factor 3/7, IRF3/7)并磷酸化IRF3/7，最后磷酸化的IRF3/7被转运到细胞核中激活IFN-I的表达^[18]。接着Janus激酶(Janus kinase, JAK)-信号转导及转录激活蛋白(signal transducer and activator of transcription, STAT)通路被IFN-I激活，进一步促进干扰素刺激基因(interferon- stimulated genes, ISGs)的表达，实现抗PRV作用^[19]。不仅如此，PRV被Toll样受体(toll-like receptor, TLR)识别后主要激活髓系分化初级反应蛋白质88 (myeloid differentiation factor 88, MyD88)、含有TIR结构域的诱导干扰素-β蛋白(Toll/IL-1R domain-containing adaptor-inducingIFN-β, TRIF)通路来激活IFN-I^[20]。MyD88的募集导致丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)、细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK)、c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)、p38和核因子-κB (nuclear factor kappa-B, NF-κB)的激活，从而控制炎性细胞因子基因的表达和产生IFN-I^[21]。然而TRIF募集最终激活NF-κB、MAPK和IRF3^[20]。DNA病毒复制过程中所产生的RNA和病毒感染过程中来源于宿主产生的RNA可启动视黄酸诱导基因I样受体(retinoic acid-induced gene-I like receptor, RLR)介导的信号通路^[22]。视黄酸诱导基因I (retinoic acid inducible gene, RIG-I)和黑素瘤分化相关基因蛋白5 (melanoma differentiation-associated gene-5, MDA-5)所募集的线粒体抗病毒信号蛋白(mitochondrial antiviral signaling protein, MAVS)能够激活肿瘤坏死因子受体相关因子(tumor necrosis factor receptor- associated factor, TRAF)、TBK1、IκB激酶(IκB kinase, Iκκ)等信号蛋白分子，并引起下游IRF3/7、NF-κB等转录因子的激活和核易位，最终引起IFN-I和促炎细胞因子的分泌以参与机体的抗病毒反应^[23]。

炎症反应对PRV感染具有一定的抑制作用，但是炎症反应过度反而会导致细胞损伤。PRV感染会激活炎症小体核苷酸结合结构域富含亮氨酸重复序列和含热蛋白结构域受体3 (nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3, NLRP3)和干扰素γ诱导蛋白16 (interferon-gamma inducible protein 16, IFI16)等^[24]，炎症小体激活半胱氨酸天冬氨酸蛋白酶1 (cysteinyl aspartate specific proteinase 1, Caspase-1)，激活后的Caspase-1可以使白细胞介素-1β (interleukin-1β, IL-1β)和白细胞介素-18 (interleukin-18, IL-18)成熟，并切割gasdermin D蛋白使IL-1β和IL-18从膜孔中间接释放，导致细胞膜通道打开发生细胞焦亡^[25]。除细胞焦亡外，PRV感染导致活性氧(reactive oxygen species, ROS)和自由基大量产生导致DNA损伤，激活线粒体依赖的细胞凋亡通路^[26]。除此之外，PRV还可以通过激活p38和JNK信号转导，促进肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)分泌，从而诱导细胞凋亡^[27]。研究表明，自噬通过增强先天免疫或帮助抗原呈递来促进宿主抗病毒防御^[28]。PRV感染对细胞自噬反应具有双重影响，在感染早期，PRV病毒不需要复制就能诱导自噬，随着病毒蛋白的表达，US3蛋白可以通过激活PRV感染细胞的蛋白激酶B (protein kinase B, Akt)/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)通路来抑制自噬水平^[29]。现有的研究表明，较多的天然生物活性分子，尤其植物类多糖、蛋白质等大分子，黄酮、酸、多肽等小分子，真菌、细菌代谢物等对PRV感染具有抑制作用。它们可以通过抑制PRV复制过程，增强IFN-I产生和分泌等宿主免疫应答，以及调节细胞凋亡和自噬过程来抑制PRV对宿主细胞的感染。本文通过整理分析这些抗PRV感染的分子及其抗病毒分子机制，期望能为伪狂犬病防控提供有用线索，并为其特效药的研发给予新的启示。

2 植物源活性分子

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在抗病毒制剂的研究过程中，因取材方便，提取简便，副作用小，抗病毒作用明显，天然植物源分子一直是研究热点。天然植物源分子可通过直接或间接作用对病毒产生抑制作用，通过对天然植物源分子抗PRV作用的研究，能辅助疫苗免疫并为病毒特效药研发奠定基础。天然植物源分子种类繁多，研究表明，多糖、蛋白等大分子，以及很多小分子黄酮、酚、生物碱等，都对PRV有一定抑制作用，在PRV防治方面有潜在的应用价值。

2.1 多糖分子

草本植物的多种成分都有较好的抗菌、抗寄生虫、抗病毒、免疫调节作用。其中，多糖的抗病毒作用研究较多，例如：海藻多糖能通过和J亚群禽白血病病毒(avian leukosis virus subgroup j, ALV-J)结合，抑制其吸附过程^[30]。不仅如此，绿海藻衍生的硫酸化多糖可抑制单纯疱疹病毒(herpes simplex virus, HSV)复制^[31]；菊花多糖及其磷酸化多糖均能减轻鸭甲型肝炎病毒(duck hepatitis a virus, DHAV)对雏鸭的肝损伤^[32]；磷酸化的党参多糖也可以通过抑制病毒复制来减少DHAV病毒颗粒的数量^[33]。

类似地，植物多糖对PRV的感染也具有抑制作用。研究发现，植物多糖主要通过直接抑制PRV感染过程，或者免疫调节、抑制凋亡、抑制自噬、减少病毒感染引起的氧化应激等间接方式抑制PRV感染。例如：桔梗的重要活性成分桔梗多糖，以剂量依赖性方式抑制PRV复制，并通过Akt/mTOR信号通路下调病毒诱导的自噬^[34]；同时，减少PRV感染导致的线粒体损伤并上调B细胞淋巴瘤-2 (B cell lymphoma-2, Bcl-2)的表达和维持线粒体膜电位(mitochondrial membrane potential, MMP)，抑制PRV诱导的细胞凋亡^[35] (表1)。中国传统的药用植物沙棘是一种开花灌木，其主要活性成分沙棘多糖可以抑制PRV吸附和进入；降低受PRV感染的细胞中的丙二醛含量和ROS，并增加超氧化物歧化酶(superoxide dismutase, SOD)活性，通过这些途径减少PRV感染引起的氧化应激^[36] (表1)。对中枢神经系统有明显的抑制和镇痛作用的三七多糖是三七的主要活性成分^[37]，体外研究表明，三七多糖可以通过抑制病毒吸附和复制发挥抗PRV作用，但其具体机制犹未可知^[38] (表1)。甘草多糖是一种常见的中药甘草提取物，研究表明，甘草多糖具有免疫调节、抗氧化^[39]、抗肿瘤^[40]、抗病毒^[41]、抗菌^[42]特性。甘草多糖在PRV感染的早期阶段，通过阻止病毒吸附和内化来抑制PRV感染，但只有在与病毒同时添加时才会显示抗病毒作用，提示其与病毒具有直接的相互作用^[43] (表1)。我国广泛种植和分布的植物板蓝根常用于治疗传染病和炎症^[44]，板蓝根多糖是板蓝根的活性成分，具有抗氧化、抗炎和抗病毒特性^[45]。树突状细胞(dendritic cell, DC)是免疫反应的关键调节剂，特别是在抗原的摄取和呈递以及免疫相关细胞因子的产生方面，成熟的DC分泌多种炎性因子，这些炎症因子在免疫应答中很重要。研究发现，PRV感染诱发了白细胞介素-12 (interleukin-12, IL-12)表达的增加，但减少了白细胞介素-6 (interleukin-6, IL-6)的表达，板蓝根多糖可以促进DC成熟，提高其分泌潜力并增强IL-12和IL-6分泌来抑制PRV感染^[46] (表1)。槐耳作为一种传统中药，用于治疗多种疾病，能增强宿主免疫力，诱导乳腺癌细胞凋亡，被认为是一种很有前景的乳腺癌辅助治疗药物^[47]。除此之外，研究发现槐耳多糖通过阻断PRV在细胞中的吸附和进入，起到抗病毒作用^[48] (表1)。

2.2 黄酮、酚、生物碱等小分子

黄酮类化合物主要通过抑制病毒吸附、进入、复制等感染过程，调节NF-κB通路以及调节炎症因子的表达等方式来抑制PRV的感染。例如，木犀草素通过抑制信号转导与转录激活因子1/3依赖性NF-κB激活，以及诱导核转录因子红系2相关因子2 (nuclear factor-erythroid 2-related factor 2, Nrf2)介导的血红素加氧酶1 (heme oxygenase 1, HO-1)表达，降低PRV感染导致的促炎介质NO、炎症细胞因子及诱生型一氧化氮合酶(inducible nitric oxide synthase, iNOS)和环氧合酶2 (cyclooxygenase-2, COX-2)的表达^[49]。不仅如此，使用木犀草素产品能推迟PRV感染小鼠临床症状的发生，提高受感染小鼠存活率的同时减少了病毒对脑组织的损害^[50] (表1)。研究发现，作为传统中药的金银花与木犀草素具有相似的抗PRV原理^[51] (表1)。从杨梅的果实中提取的杨梅素，对PRV有直接灭活作用，能抑制其吸附和进入过程；不仅能激活被PRV抑制的cGAS-STING信号通路^[52]、调节NF-κB/MAPK信号通路，还能调节病毒感染引起的炎症反应和细胞凋亡；在PRV感染小鼠模型中，杨梅素可提高感染PRV小鼠的存活率，显著降低肾、肝、肺、脾、脑中的病毒载量，同时杨梅素的处理改善了PRV感染引起的病理变化^[53] (表1)。与木犀草素和杨梅素相比，辣蓼中黄酮类化合物的乙酸乙酯馏分不仅能显著抑制NO合成，下调COX-2、iNOS和炎性细胞因子的表达和分泌，还能减少NF-κB p65向细胞核的易位和MAPK磷酸化^[54]。近期研究发现，辣蓼黄酮对Nrf2信号通路和组蛋白乙酰化修饰具有调控作用，其通过该调控作用缓解PRV感染小鼠诱导的氧化应激^[55] (表1)。枳实、桑树和银杏等植物中存在的黄酮醇类物质二氢霉素可以直接杀伤病毒，也可抑制病毒吸附和复制过程；能逆转由PRV感染引起的NF-κB通路的抑制状态来增强细胞免疫力；同时也可以通过NF-κB途径下调炎症基因TNF-α、白细胞介素-1α (interleukin-1α, IL-1α)和IL-6等的基因表达水平，防止PRV感染细胞引起过度炎症反应；另外，作为促凋亡蛋白Bcl2关联X蛋白(Bcl 2 associated X protein, Bax)的化学抑制剂，抑制Bax和细胞色素c的释放，并发挥抗凋亡作用促进受感染细胞的凋亡来抑制病毒增殖^[56] (表1)。山奈根茎中提取的山奈酚，具有抗炎、抗氧化和抗病毒作用。实验表明，山奈酚抑制了PRV IE180蛋白的转录从而抑制PRV复制过程；潜伏相关转录体(latency associated transcript, LAT)在PRV潜伏期的建立、维持和再激活过程中发挥着重要作用，体内研究发现，山奈酚的使用使大脑中LAT的转录水平受到抑制，从而抑制了PRV潜伏期；此外，山奈酚有效抑制大脑中PRV的复制^[57] (表1)。蔬菜、水果和谷物中分布最广泛的植物类黄酮槲皮素，具有优异的抗氧化、抗凋亡、抗感染、抗炎和抗菌等特性。实验表明，注射槲皮素可降低小鼠死亡率及脑组织中的PRV复制，不仅如此，还能通过阻断nectin-1与gD的结合来抑制PRV的吸附；另外槲皮素可大大减少ROS的分泌，减轻PRV感染引起的氧化应激^[58] (表1)。补骨脂查尔酮具有多种生物活性，如抗细菌、抗真菌和抗癌活性。在目前的研究中，证明其可以通过阻断病毒介导的细胞融合来抑制PRV感染^[59] (表1)。

植物酚类化合物的抗病毒作用也有较多研究，例如：姜黄主要成分中的一种酸性酚类化合物姜黄素，具有抗炎、神经保护和抗病毒活性，可以穿过血脑屏障^[60]。脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)是一种神经营养因子，具有神经营养、抗细胞凋亡、抗氧化和抑制自噬的作用。PRV感染会导致氧化应激和对神经元的损害，姜黄素可以通过抑制BDNF的减少，达到保护神经元作用^[61]。不仅如此，姜黄素还可以通过改善线粒体功能和AMP活化蛋白激酶(AMP-activated protein kinase, AMPK)/NF-κB p65能量代谢相关途径进行细胞表型转换，抵抗PRV感染导致的神经元受损；体内实验发现，姜黄素的使用可以减轻PRV感染导致的脑炎的病理变化^[62] (表1)。从牛至草中提取的挥发性芳香油牛至精油，其主要成分为香芹酚或百里香酚，通过抗PRV胞内增殖，在高浓度下直接杀灭PRV来抑制感染；还可以上调TNF-α、β干扰素(interferon-β, IFN-β)、γ干扰素(interferon-γ, IFN-γ)和IL-12的分泌^[63] (表1)。非类黄酮多酚化合物白藜芦醇通过靶向PRV IE180蛋白位点来抑制IE180的转录激活活性从而抑制PRV的复制^[64]。免疫调节方面，白藜芦醇可以提高TLR4、Iκκ、核因子κB抑制蛋白α (inhibitor of NF-κB alpha, IκBα)、NF-κB和JNK的蛋白质水平；不仅如此，小鼠体内实验还发现白藜芦醇可以通过上调T淋巴细胞亚群来增强免疫功效^[65]。同时，研究还发现白藜芦醇可以抑制IκB激酶降解的能力^[66]。更重要的是，研究发现白藜芦醇能有效降低PRV感染仔猪的死亡率并提高其生长性能，减轻脑部炎症^[67] (表1)。

生物碱具有良好的生物活性，在抗菌和增强抗生素活性方面具有突出贡献^[79]。生物碱的抗病毒作用研究也是热门之一。研究发现，β-咔啉衍生物在植物、哺乳动物和微生物中广泛分布，具有广泛的生物活性。双特异性酪氨酸磷酸化调节激酶1A (dual specificity tyrosine phosphorylation regulated kinase 1A, DYRK1A)是CMGC组蛋白激酶中的一种，是多种细胞过程的关键调节分子，可通过调节糖原合酶激酶3β活性来影响巨胞饮作用。实验表明，β-咔啉生物碱能抑制DYRK1A从而抑制细胞对PRV的巨胞饮作用^[68] (表1)。类似地，(S)-10-羟基喜树碱可以通过阻断病毒基因组复制和靶向DNA拓扑异构酶1 (DNA topoisomerase 1, TOP1)抑制PRV复制；诱导DNA损伤反应刺激抗病毒先天免疫，增强INF-β反应；更重要的是，该生物碱可有效缓解PRV感染诱导的小鼠肺和脑组织的临床症状和组织病理变化^[69] (表1)。

除了以上研究较多的分类外，还有很多其他类型的天然化合物。例如，姜科植物产生的吉马酮，是一种具有抗肿瘤、抗病毒、抗菌和抗炎特性的单环双萜烯，在PRV复制的早期阶段通过影响细胞抗病毒机制来抑制PRV复制^[70] (表1)。天然蒽醌衍生物大黄素，是大黄、何首乌等的活性成分，具有多种抗病毒活性，能在复制阶段抑制PRV增殖；通过抑制PRV基因表达、PRV gB和gD表达，以及减轻PRV诱导的细胞凋亡发挥抗病毒作用；体内实验更是证实，大黄素显著抑制了PRV在小鼠心脏、肝脏、脑、肾和肺中的复制，减轻了PRV感染引起的组织和器官损伤，使小鼠的存活率提高^[71] (表1)。银杏叶中提取的天然产物银杏酸，可以通过抑制PRV晚期基因的转录有效抑制其在体内外的复制，并且银杏酸可以降低PRV在各组织中的病毒载量，提高小鼠的存活率^[72] (表1)。提取自传统中药蟾酥的蟾毒灵是一种类固醇，可以通过干扰PRV复制周期的进入阶段，对PRV复制起到显著的抑制作用，并且降低感染小鼠的死亡率^[73] (表1)。在可食用蔬果中广泛存在白皮杉醇，可降低PRV基因的转录水平；减少PRV诱导的细胞凋亡；提高小鼠血清中白细胞介素-4 (interleukin-4, IL-4)、TNF-α和IFN-γ水平，发挥抗PRV作用；体内实验表明，白皮杉醇可延缓发病，降低脑、肾病毒载量，提高小鼠存活率^[74] (表1)。研究发现，没食子儿茶素没食子酸酯可以通过抑制PRV的进入和释放阶段来有效抑制PRV的复制^[75]。随着抗病毒药物的迫切需求，具有高生物相容性和抗病毒作用的抗病毒材料引起了人们的广泛关注，将没食子酸转化为生物相容性石墨烯量子点的形式，可以缓解PRV感染小鼠的临床症状并降低死亡率，对PRV的抗病毒活性具有增强作用^[76] (表1)。

除以上已知成分的植物类分子外，还有许多未知具体成分的植物提取物具有良好的抗PRV作用。蒲公英是一种传统的药食植物，具有广谱抗菌、抗氧化作用。通过煎煮法获得的蒲公英水提取物在体内外均对PRV感染具有较强的抑制活性，能阻断PRV吸附和复制，降低PRV基因表达；不仅如此，还能保护PRV感染的小鼠，提高其存活率，减少病理组织变化，并能调节细胞因子的产生，以抵抗PRV感染^[77] (表1)。生活中常食用的蔬菜也具有良好抗PRV作用，例如：纳豆是一种由大豆制成的发酵食品，研究发现，纳豆提取物能通过蛋白水解作用使PRV失活，使得PRV在小鼠体内失去感染性^[78] (表1)。

3 动物源活性因子或分子

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PRV感染会导致宿主启动一系列免疫反应，导致IFN-I、ISGs、炎性细胞因子等活性因子或分子的表达，这些因子在抑制PRV感染过程中十分重要^[17]。宿主防御肽也是抗感染免疫反应中的重要组成部分^[80]，是几乎所有生命形式中常见的宿主防御分子。宿主防御肽具有良好的抗菌、抗寄生虫和抗病毒活性，不易产生耐药性，这类动物源活性分子被证明具有较好的抗PRV作用，可以通过直接破坏病毒结构，或者抑制PRV感染过程，增强宿主免疫反应等方式来抗PRV感染。因此，以上动物源活性因子或分子在PRV防治方面也有潜在的应用价值。

3.1 IFN-I及ISGs蛋白

IFN-I是一种信号因子，具有抗病毒、抗增殖和免疫调节作用^[81]，α干扰素(interferon-α, IFN-α)是IFN-I中的一种，主要来自血浆细胞样树突状细胞。IFN-α能有效抑制PRV感染。有研究发现，分析猪α干扰素(interferon)的氨基酸序列，调整PoIFN-α亚型序列，获得序列突变的PoIFN-α突变体PoIFN-α-156s，具有较高的抗病毒活性，可以在体外以剂量依赖的方式抑制PRV复制，还可以降低小鼠体内病毒载量^[82] (表2)。不仅如此，重组的IFN-α也可缓解PRV感染的症状，能减少PRV的体内复制^[83]。将猪IFN-α和白细胞介素-2 (interleukin-2, IL-2)重组，获得融合蛋白(rPoIFNα+IL-2)，该蛋白对细胞无毒性作用且能抑制PRV的复制，同时能增强外周血单核细胞的增殖；使ISGs的表达量增加，增强了IFN-γ和白细胞介素-10 (interleukin-10, IL-10)的表达水平，并抑制IL-1β和IL-6的表达；体内实验表明该蛋白能缓解感染PRV小鼠的临床症状并降低小鼠死亡率^[84] (表2)。IFN-β在PRV感染引起的宿主先天免疫通路中发挥重要作用，增强IFN-β的表达能有效抑制PRV。含非POU结构域的八聚体结合蛋白(non-pou domain-containing octamer-binding protein, NONO)，作为果蝇行为/人类剪接蛋白家族(drosophila behavior/human splicing family, DBHS)中的一员，在转录调控、RNA剪接、DNA修复中发挥着关键作用；猪NONO(sNONO)证实能增强IFN-β启动子的激活和IFN-β的表达，并正向调节ISGs转录水平，因而具有拮抗PRV感染的作用^[85] (表2)。除了传统的IFN-I外，研究发现猪的δ8干扰素(interferon-δ8, IFN-δ8)是一种新型IFN-I，在猪IFN-δ亚型中具有最强的抗病毒和免疫调节活性^[86]。实验表明，猪IFN-δ8显著增加了8个ISGs的表达以抵抗病毒感染，猪IFN-δ8对PRV感染具有显著的保护作用^[87] (表2)。

ISGs及其表达产物具有抗病毒、免疫调控等多种生物学功能，是干扰素发挥功能的重要效应分子，是宿主发挥抗PRV作用的效应蛋白。例如，IFN-I和IFN-III系统的关键抗病毒效应蛋白黏性抗病毒蛋白(myxovirus resistance, Mx)蛋白，通过阻断病毒早期复制来抑制病毒感染^[88]，因其在脊椎动物中高度保守，在跨物种防御中发挥重要作用。研究表明，猪的Mx蛋白1 (poMx1)通过抑制早期基因UL54和EP0的合成抑制PRV的增殖过程，同时可以抑制PRV DNA输送到细胞核，实现对PRV复制的抑制作用^[89] (表2)。干扰素诱导的跨膜蛋白(interferon- induced transmembrane protein, IFITM)可以通过中断病毒包膜和细胞膜之间的膜融合来抑制病毒进入宿主细胞，同时减少传染性病毒粒子的产生^[90]。研究表明，猪的干扰素诱导的跨膜蛋白1 (pIFITM1)通过亚细胞定位限制PRV进入^[91] (表2)。干扰素刺激的泛素样蛋白ISG15在病毒感染期间高度增加，参与干扰素介导的抗病毒免疫反应。研究发现，猪ISG15在PRV感染的早期阶段上调，其过表达能降低PRV的病毒滴度和mRNA水平从而抑制PRV复制；不仅如此，ISG15表达增加会诱导IFN-β的表达增加以及干扰素刺激应答元件(interferon stimulated response element, ISRE)启动子的激活^[92] (表2)。

3.2 宿主防御肽

近些年研究发现，多种动物源宿主防御肽具有良好的抗病毒的作用，抗菌肽Protegrines、人抗菌肽LL-37、temporin B (TB)被证实能有效抑制HSV的感染^[97]，除此之外，LL-37对丙型肝炎病毒(hepatitis c virus, HCV)^[98]、甲型流感病毒(influenza a virus, IAV)、牛痘病毒(vaccinia virus, VV)、呼吸道合胞病毒(respiratory syncy-tial virus, RSV)等多种病毒感染也具有抑制作用^[99]。基于抗菌肽良好的抗病毒活性，本课题组对抗菌肽抑制PRV作用也做了初步研究。

一种禽源抗微生物肽(cathelicidin B1, CATH-B1)能显著抑制PRV感染，通过破坏PRV的病毒结构直接灭活病毒，抑制病毒吸附和进入；还可以通过激活TLR4、引起内体酸化，然后TLR4与JNK相互作用激活IRF3/IFN-β通路，诱导IRF3的磷酸化，进一步导致IFN-β的产生来调节宿主免疫反应；不仅如此，在小鼠体内实验中还发现，CATH-B1对小鼠具有一定的治疗作用^[93] (表2)。另外，一种由鱼肥大细胞产生的防御肽Piscidin1，也被研究人员证明以剂量依赖的方式与病毒颗粒直接相互作用来抑制PRV；还可以保护细胞免受PRV诱导的凋亡；体内实验表明，使用该肽后还能降低小鼠死亡率^[94] (表2)。猪β-防御素2 (porcine β-defensin-2, PBD-2)是一种具有多种功能的富含抗菌胱氨酸的阳离子肽，其具有良好的抗菌活性，可以调节宿主免疫反应。研究发现，PBD-2可以抑制细胞中的PRV增殖，保护小鼠免受PRV感染^[95] (表2)。小鼠肺组织中的一种下调的生物肽AGDP显示对PRV感染具有体外治疗作用，AGDP通过抑制TNF-α和白细胞介素-8 (interleukin-8, IL-8)的表达及PRV感染后IκBα的降解和p65的磷酸化水平来减轻PRV感染导致的炎症反应^[96] (表2)。

4 微生物源活性分子

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药物真菌一直在全球范围内被广泛应用，尤其像中医中常用的药物如灵芝、冬虫夏草等都属于真菌，对于治疗疾病有良好的作用。真菌自身及其分泌产物蛋白质、多糖、生物碱等物质有较好的抗癌、抗炎、抗菌作用^[100]。不仅如此，真菌的抗病毒作用研究也是热点。例如，香菇菌丝体提取物能在病毒复制晚期阶段阻断HSV-1的复制^[101]，从灵芝中分离的酸性蛋白结合多糖，可以阻碍病毒与细胞质膜的相互作用，从而抑制病毒感染^[102]。冬虫夏草中的新型脂肪酸能抑制IAV (H1N1)诱导的促炎反应^[103]。因此，真菌的价值已不仅仅是在食用方面，对于抗病毒作用的研究使得真菌具有更深的疾病防控意义。

近些年，对病毒和真菌毒素之间相互作用的潜在机制的研究，使得我们对霉菌有了新的认知^[104]。研究表明，部分霉菌具有抗PRV作用。从九江链霉菌的肉汤中分离出的苯并异环二级代谢物4 (病毒霉素)对PRV表现出优异的抑制效果，证明氯原子和四氢喹啉骨架是抗病毒活动的重要活性部分^[105] (表3)。T-2毒素(T2)是一种重要的霉菌毒素，广泛传播于食品和饲料中，对哺乳动物表现出高毒性。研究发现，伴随着氧化应激和凋亡信号通路的下调，低浓度的T2能抑制细胞中PRV的复制^[106] (表3)。由阿维链霉菌发酵产生的半合成大环内酯类多组分抗生素伊维菌素，是一种由输入蛋白-α/β介导的核输入广谱抑制剂。研究表明，由于PRV的UL42需要输入蛋白-α/β介导进行核运输，伊维菌素的使用使得PRV UL42在细胞核的定位被中断，使病毒复制显著减少，除此之外，伊维菌素的使用提高了受感染小鼠的存活率^[107] (表3)。萘吡酮霉素A4源自Streptomyces kebangsaanensis，对PRV蛋白有很强的抑制作用^[108] (表3)。

细菌代谢物一直被用于抗菌、抗寄生虫研究，抗病毒研究较少。研究表明，细菌代谢物也具有良好的抗病毒特性，例如：地衣芽孢杆菌的外聚物可有效抑制HSV和水泡性口炎病毒(vesicular stomatitis virus, VSV)进入，但对无包膜病毒无效^[112]。益生菌及其代谢产物的抗PRV作用也越来越被重视，例如：枯草芽孢杆菌是一种具有重要商业价值的益生菌，可产生具有抗菌、抗真菌和抗炎活性的次生代谢产物。研究发现，枯草芽孢杆菌L2的次级代谢物能有效地阻碍PRV的结合、进入和复制；体内实验表明，口服枯草芽孢杆菌L2的代谢物可保护小鼠免受致命的PRV感染，并降低体内病毒载量^[109] (表3)。乳酸菌作为益生菌之一，具有调节肠道菌群平衡、抑制病原菌生长和病毒增殖、提高自身免疫力等有益特性。研究发现，分离的植物乳杆菌HN-11和干酪乳杆菌HN-12能抑制细胞中PRV的增殖；通过动物实验可以发现，提前向小鼠补充乳酸菌分离株的上清液可延缓病程并减少病毒含量^[110] (表3)。另外，来自内生真菌Talaromyces purpureogenus的多环萜类化合物，对PRV有剂量依赖性抑制作用^[111] (表3)。

5 总结与展望

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伪狂犬病是威胁生猪生产的重要疫病，随着PRV毒株不断变异，疫苗免疫的传统方案已不能满足如今快速变异的病毒。不仅如此，鉴于PRV感染人病例的报道，对PRV的防控不足或将导致其威胁人类健康。研究发现，来源于植物的多种生物活性分子对PRV具有抑制作用，例如桔梗多糖、沙棘多糖、三七多糖等多糖分子，以及木犀草素、槲皮素、二氢霉素等小分子化合物，可通过直接杀伤PRV或调节宿主免疫抑制PRV感染。另外，动物源活性分子IFN-I及ISGs介导的先天免疫是宿主抵抗PRV感染的重要途径，研究表明，宿主IFN-I和多种ISGs蛋白具有抑制PRV感染作用。宿主防御肽是近些年的研究热点，研究发现CATH-B1等宿主防御肽能有效抑制PRV感染。另外，某些细菌和真菌代谢物也具有抗PRV作用，有望将传统意义上的有害微生物转变成抗病毒制剂。由此可见，抗PRV感染的天然生物活性分子来源广泛、种类丰富、作用机制多样，从植物、动物和微生物中筛选抗病毒天然生物活性分子具有极大的前景。

本课题组成员前期在针对动物源活性分子抑制PRV感染的作用研究中，发现一种抗微生物肽CATH-B1能够通过直接破坏PRV粒子结构，激活宿主TLR4/JNK/IRF3通路并诱导Ⅰ型IFNs信号通路激活发挥抗病毒作用。未来，本课题组研究人员将进一步针对微生物源分子的抗PRV感染作用展开研究，尤其是体内抗PRV作用的研究。

目前发现的抗PRV天然生物活性分子在体外均表现出良好的抗PRV作用，部分分子在小鼠上进行了体内抗PRV作用验证，白藜芦醇甚至在仔猪上进行了验证，均表现出显著的抗PRV作用。然而，鉴于这些体内研究的结果多数来自小鼠实验，相关分子在生猪养殖中是否有相同的抑制作用尚需进一步验证。目前，抗PRV天然生物活性分子相关研究尚处于起步阶段，还未真正进入临床评价的阶段。由于天然产物的生物活性成分筛选难度大、合成成本高，新药研发具有成本高和周期长的特点，这些药物分子走上临床还要面临诸多困难和挑战。然而，随着各类抗PRV天然活性分子的不断发现，再结合现代药理学和化学生物学等新技术的使用，有望将这些分子开发成预防和治疗PRV的新制剂，助力临床上PRV的防控与净化。

基金

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国家自然科学基金(32372982)
中央高校基本科研业务费专项资金(SWU-KT22016)
国家生猪技术创新中心项目(NCTIP-XD/C17)
重庆生猪产业技术体系项目(20211105)

参考文献

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文献

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参考文献引证文献

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2024年第64卷第10期

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doi: 10.13343/j.cnki.wsxb.20240207

接收时间：2024-03-29
首发时间：2026-03-21
出版时间：2024-07-02

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收稿日期：2024-03-29
录用日期：2024-06-28

基金

National Natural Science Foundation of China(32372982)

国家自然科学基金(32372982)

Fundamental Research Funds for the Central Universities(SWU-KT22016)

中央高校基本科研业务费专项资金(SWU-KT22016)

National Center of Technology Innovation for Pigs(NCTIP-XD/C17)

国家生猪技术创新中心项目(NCTIP-XD/C17)

Chongqing Pig Industry Technology System(20211105)

重庆生猪产业技术体系项目(20211105)

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西南大学动物医学院, 动物健康与动物性食品安全国际合作联合实验室, 重庆 400715

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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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Classification	Name	In vivo/In vitro	Pathway or mechanism of action	References
Polysaccharide	Platycodon grandiflorus polysaccharide	In vitro	Inhibit the replication of PRV Reduce mitochondrial damage and the levels of mitochondrial pathway-induced apoptosis Downregulate PRV-induced autophagy via the Akt/mTOR pathway	[34-35]
Hippophae rhamnoides polysaccharide	In vitro	Inhibit the adsorption and entry of PRV Reduce PRV infection-induced oxidative stress	[36]
Panax notoginseng polysaccharide	In vitro	Inhibit the adsorption and replication of PRV	[37-38]
Glycyrrhiza polysaccharide	In vitro	Inhibit the adsorption and internalization of PRV	[39-43]
Isatis root polysaccharide	In vitro	Inhibit the replication of PRV Stimulate the maturation of DCs, induce IL-12 and IL-6 secretion	[44-46]
Huaier polysaccharide	In vitro	Inhibit the adsorption and entry of PRV	[47-48]
Flavonoid	Luteolin	Mice	Diminish the proinflammatory mediators NO, inflammatory cytokines and the expression of their regulatory genes, iNOS and COX-2 Inhibit STAT1/3 dependent NF-κB activation and induce Nrf2 mediated HO-1 expression	[49-50]
Flos Lonicerae Japonicae water extract	In vitro	Reduce the expression of proinflammatory mediators and inflammatory cytokines, such as COX-2 and iNOS, through the suppression of the JAK/STAT1/3-dependent NF-κB pathway and the induction of HO-1 expression	[51]
Myricetin	Mice	Directly inactivate virus Inhibit the adsorption and entry of PRV Activate the cGAS/STING pathway Regulate NF-κB/MAPK pathway, inflammatory response and apoptosis	[52-53]
Ethyl acetate fraction of flavonoids from Polygonum hydropiper L	Mice	Inhibit NO synthesis and downregulate the expression and secretion of COX-2, iNOS and inflammatory cytokines Reduce translocation of NF-κB p65 to the nucleus and MAPK phosphorylation Regulate Nrf2 signaling pathway and histone acetylation, and alleviate oxidative stress induced by PRV-infected mice	[54-55]
Dihydromyricetin	In vitro	Directly inactive virus Inhibit the adsorption and replication of PRV Activate NF-κB pathway and downregulate expression levels of inflammatory genes TNF-α, IL-1α, and IL-6 via the NF-κB pathway Inhibit the release of Bax and cytochrome c and exert anti-apoptotic effects	[56]
Kaempferol	Mice	Inhibit the IE180 transcription Inhibit transcription levels of LAT	[57]
Quercetin	Mice	Inhibit PRV adsorption by blocking the binding of nectin-1 to gD Reduce ROS secretion and alleviate oxidative stress caused by PRV infection	[58]
Isobavachalcone	In vitro	Impair virus-induced cell-to-cell fusion	[59]
Phenols	Curcumin	Mice	Inhibit the reduction of BDNF to protect neurons Improve mitochondrial function and AMPK/NF-κB p65 energy metabolism	[60-62]
Oregano essential oil	In vitro	Directly kill virus at high concentration Up-regulate the expression of TNF-α, IFN-β, IFN-γ, and IL-12	[63]
Resveratrol	Mice, piglets	Inhibit the IE180 transcription Increase the protein levels of TLR4, Ikk, IκBα, NF-κB, JNK and inhibit the degradation of IκB kinase	[64-67]
Alkaloid	β-carboline derivative	In vitro	Inhibit the macropinocytosis-dependent entry of PRV into cells by inhibiting DYRK1A	[68]
(S)-10-hydroxycamptothecin	Mice	Inhibit PRV replication by blocking PRV genome replication and targeting DNA topoisomerase 1 (TOP1) Induce DNA damage response, stimulate antiviral innate immunity and enhance INF-β response.	[69]
Monocyclic sesquiterpenoids	Germacrone	In vitro	Inhibit the replication of PRV	[70]
Natural anthraquinone derivative	Emodin	Mice	Inhibit the replication of PRV Inhibit the expression of PRV gene and the protein expression of PRV gB and gD Inhibit the PRV-induced apoptosis	[71]
Acid	Ginkgolic acid	Mice	Inhibit the late gene transcription of PRV	[72]
Steroid	Bufalin	Mice	Inhibit the entry of PRV	[73]
Stilbene-like compound	Piceatannol	Mice	Reduce the transcription levels of PRV genes Reduce PRV-induced apoptosis Increase the expression of IL-4, TNF-α, and IFN-γ	[74]
Ester	Gallocatechin gallate	Mice	Inhibit the entry and release of PRV	[75-76]
Extract	Dandelion aqueous extract	Mice	Inhibit the adsorption and replication of PRV Decrease the expression of PRV gene Regulate the production of cytokines	[77]
Natto extract	Mice	Inactivate PRV via proteolysis	[78]

Classification

Name

In vivo/In vitro

Pathway or mechanism of action

References

Polysaccharide

Platycodon grandiflorus polysaccharide

In vitro

Inhibit the replication of PRV Reduce mitochondrial damage and the levels of mitochondrial pathway-induced apoptosis Downregulate PRV-induced autophagy via the Akt/mTOR pathway

[34-35]

Hippophae rhamnoides polysaccharide

In vitro

Inhibit the adsorption and entry of PRV Reduce PRV infection-induced oxidative stress

[36]

Panax notoginseng polysaccharide

In vitro

Inhibit the adsorption and replication of PRV

[37-38]

Glycyrrhiza polysaccharide

In vitro

Inhibit the adsorption and internalization of PRV

[39-43]

Isatis root polysaccharide

In vitro

Inhibit the replication of PRV Stimulate the maturation of DCs, induce IL-12 and IL-6 secretion

[44-46]

Huaier polysaccharide

In vitro

Inhibit the adsorption and entry of PRV

[47-48]

Flavonoid

Luteolin

Mice

Diminish the proinflammatory mediators NO, inflammatory cytokines and the expression of their regulatory genes, iNOS and COX-2 Inhibit STAT1/3 dependent NF-κB activation and induce Nrf2 mediated HO-1 expression

[49-50]

Flos Lonicerae Japonicae water extract

In vitro

Reduce the expression of proinflammatory mediators and inflammatory cytokines, such as COX-2 and iNOS, through the suppression of the JAK/STAT1/3-dependent NF-κB pathway and the induction of HO-1 expression

[51]

Myricetin

Mice

Directly inactivate virus Inhibit the adsorption and entry of PRV Activate the cGAS/STING pathway Regulate NF-κB/MAPK pathway, inflammatory response and apoptosis

[52-53]

Ethyl acetate fraction of flavonoids from Polygonum hydropiper L

Mice

Inhibit NO synthesis and downregulate the expression and secretion of COX-2, iNOS and inflammatory cytokines Reduce translocation of NF-κB p65 to the nucleus and MAPK phosphorylation Regulate Nrf2 signaling pathway and histone acetylation, and alleviate oxidative stress induced by PRV-infected mice

[54-55]

Dihydromyricetin

In vitro

Directly inactive virus Inhibit the adsorption and replication of PRV Activate NF-κB pathway and downregulate expression levels of inflammatory genes TNF-α, IL-1α, and IL-6 via the NF-κB pathway Inhibit the release of Bax and cytochrome c and exert anti-apoptotic effects

[56]

Kaempferol

Mice

Inhibit the IE180 transcription Inhibit transcription levels of LAT

[57]

Quercetin

Mice

Inhibit PRV adsorption by blocking the binding of nectin-1 to gD Reduce ROS secretion and alleviate oxidative stress caused by PRV infection

[58]

Isobavachalcone

In vitro

Impair virus-induced cell-to-cell fusion

[59]

Phenols

Curcumin

Mice

Inhibit the reduction of BDNF to protect neurons Improve mitochondrial function and AMPK/NF-κB p65 energy metabolism

[60-62]

Oregano essential oil

In vitro

Directly kill virus at high concentration Up-regulate the expression of TNF-α, IFN-β, IFN-γ, and IL-12

[63]

Resveratrol

Mice, piglets

Inhibit the IE180 transcription Increase the protein levels of TLR4, Ikk, IκBα, NF-κB, JNK and inhibit the degradation of IκB kinase

[64-67]

Alkaloid

β-carboline derivative

In vitro

Inhibit the macropinocytosis-dependent entry of PRV into cells by inhibiting DYRK1A

[68]

(S)-10-hydroxycamptothecin

Mice

Inhibit PRV replication by blocking PRV genome replication and targeting DNA topoisomerase 1 (TOP1) Induce DNA damage response, stimulate antiviral innate immunity and enhance INF-β response.

[69]

Monocyclic sesquiterpenoids

Germacrone

In vitro

Inhibit the replication of PRV

[70]

Natural anthraquinone derivative

Emodin

Mice

Inhibit the replication of PRV Inhibit the expression of PRV gene and the protein expression of PRV gB and gD Inhibit the PRV-induced apoptosis

[71]

Acid

Ginkgolic acid

Mice

Inhibit the late gene transcription of PRV

[72]

Steroid

Bufalin

Mice

Inhibit the entry of PRV

[73]

Stilbene-like compound

Piceatannol

Mice

Reduce the transcription levels of PRV genes Reduce PRV-induced apoptosis Increase the expression of IL-4, TNF-α, and IFN-γ

[74]

Ester

Gallocatechin gallate

Mice

Inhibit the entry and release of PRV

[75-76]

Extract

Dandelion aqueous extract

Mice

Inhibit the adsorption and replication of PRV Decrease the expression of PRV gene Regulate the production of cytokines

[77]

Natto extract

Mice

Inactivate PRV via proteolysis

[78]

Classification	Name	In vivo/in vitro	Pathway or mechanism of action	References
IFN-Ⅰ and ISGs proteins	Porcine IFN-α-156s	Mice	Inhibit the replication of PRV	[82]
	Porcine IFNα+IL-2	Mice	Enhance the proliferation of peripheral blood mononuclear cells Increase the expression of ISGs, IFN-γ, IL-10, and inhibit the expression of IL-1β and IL-6	[83-84]
Swine NONO	In vitro	Enhance the activation of IFN-β promoter and IFN-β expression	[85]
Porcine IFN-δ8	In vitro	Increase the expression of ISGs Positively regulate the ISGs transcription levels	[86-87]
Mx protein	In vitro	Inhibit the synthesis of early genes UL54 and EP0 Inhibit PRV DNA transport to the nucleus	[88-89]
Porcine IFITM1	In vitro	Restrict PRV entry	[90-91]
Porcine ISG15	In vitro	Decrease the viral titer and mRNA levels of PRV Increase expression of IFN-β and activate interferon stimulated response element (ISRE) promoters	[92]
Host defense peptides	Cathelicidin-B1	Mice	Inhibit pseudorabies virus infection via direct interaction and TLR4/JNK/IRF3-mediated interferon activation	[93]
Piscidin1	Mice	Direct interact with viral particles to inhibit PRV Inhibit PRV-induced apoptosis	[94]
Porcineβ-defensin-2	Mice	Inhibit PRV proliferation in cells	[95]
AGDP	In vitro	Inhibit the expression of TNF-α and IL-8 Inhibit the degradation of IκBα and the phosphorylation level of p65 after PRV infection	[96]

Classification

Name

In vivo/in vitro

Pathway or mechanism of action

References

IFN-Ⅰ and ISGs proteins

Porcine IFN-α-156s

Mice

Inhibit the replication of PRV

[82]

Porcine IFNα+IL-2

Mice

Enhance the proliferation of peripheral blood mononuclear cells Increase the expression of ISGs, IFN-γ, IL-10, and inhibit the expression of IL-1β and IL-6

[83-84]

Swine NONO

In vitro

Enhance the activation of IFN-β promoter and IFN-β expression

[85]

Porcine IFN-δ8

In vitro

Increase the expression of ISGs Positively regulate the ISGs transcription levels

[86-87]

Mx protein

In vitro

Inhibit the synthesis of early genes UL54 and EP0 Inhibit PRV DNA transport to the nucleus

[88-89]

Porcine IFITM1

In vitro

Restrict PRV entry

[90-91]

Porcine ISG15

In vitro

Decrease the viral titer and mRNA levels of PRV Increase expression of IFN-β and activate interferon stimulated response element (ISRE) promoters

[92]

Host defense peptides

Cathelicidin-B1

Mice

Inhibit pseudorabies virus infection via direct interaction and TLR4/JNK/IRF3-mediated interferon activation

[93]

Piscidin1

Mice

Direct interact with viral particles to inhibit PRV Inhibit PRV-induced apoptosis

[94]

Porcineβ-defensin-2

Mice

Inhibit PRV proliferation in cells

[95]

AGDP

In vitro

Inhibit the expression of TNF-α and IL-8 Inhibit the degradation of IκBα and the phosphorylation level of p65 after PRV infection

[96]

Classification	Name	In vivo/In vitro	Pathway or mechanism of action	References
Mold metabolites	4 virantmycin	In vitro	Mechanism unknown	[105]
	T-2 toxin	In vitro	Inhibit the replication of PRV Inhibit oxidative stress and apoptosis signaling pathways	[106]
	Ivermectin	Mice	Interrupt the localization of PRV UL42 in the nucleus	[107]
	Napyradiomycin A4	In vitro	/	[108]
Bacterial metabolites	Secondary metabolites of Bacillus subtilis L2	Mice	Inhibit the adsorption, entry and replication of PRV	[109]
	Lactobacillus isolates	Mice	Inhibit PRV proliferation in cells	[110]
	Polycyclic meroterpenoids, talaromyolides E−K	In vitro	It has a dose-dependent inhibitory effect on PRV	[111]

Classification

Name

In vivo/In vitro

Pathway or mechanism of action

References

Mold metabolites

4 virantmycin

In vitro

Mechanism unknown

[105]

T-2 toxin

In vitro