埃博拉病毒糖蛋白免疫抑制结构域N端和c端不同的免疫特性

IF 4.7 1区 生物学 Q1 MICROBIOLOGY
mBio Pub Date : 2025-10-09 DOI:10.1128/mbio.02278-25
Mathieu Iampietro, Sivakumar Periasamy, Philipp A Ilinykh, Yuan Qiu, Yakun Liu, Abhinit Nagar, Bin Gong, Alexander Bukreyev
{"title":"埃博拉病毒糖蛋白免疫抑制结构域N端和c端不同的免疫特性","authors":"Mathieu Iampietro, Sivakumar Periasamy, Philipp A Ilinykh, Yuan Qiu, Yakun Liu, Abhinit Nagar, Bin Gong, Alexander Bukreyev","doi":"10.1128/mbio.02278-25","DOIUrl":null,"url":null,"abstract":"<p><p>Ebola virus (EBOV) causes a severe human disease with high lethality. Pathogenesis of EBOV disease is characterized by a paradoxical combination of hyperinflammation and immunosuppression. EBOV has a single envelope glycoprotein (GP), which is a type I transmembrane protein with strong immunomodulatory effects. GP contains a conserved immunosuppressive domain (ISD) with a high similarity to ISDs of envelope proteins retroviruses. To investigate the effects of ISD, a set of 17 EBOV viral-like particle (VLP) constructs containing the entire EBOV nucleoprotein, VP40, and GP with single alanine or glycine substitutions in each position of ISD was generated and tested in human peripheral blood mononuclear cells (PBMCs). Wild-type VLPs induced inflammatory responses; however, when added to pre-stimulated cells, they reduced inflammation, thus exerting immunosuppressive properties. Substitution of lysine at ISD position 5 (Lys-5) increased anti-inflammatory properties by reducing proliferative responses of VLPs and also reducing nuclear factor of activated T-cells 1 (NFAT1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. In contrast, substitution of tryptophan at position 14 (Trp-14) increased both the pro-inflammatory and the proliferative responses and the adhesion of VLP-infected human monocytes to microvascular endothelial cells. Thus, the ISD N- and C-termini have pro- and anti-inflammatory properties, respectively, suggesting their unique implications in the EBOV pathogenesis. Furthermore, the immunomodulating effects of ISD were also mediated by shed GP, which is abundant in the medium. These data may be useful for the development of treatments for diseases caused by EBOV by targeting the ISD.IMPORTANCEOur data suggest that the ISD N-terminus plays a role in activating immune cells and pro-inflammatory response. In contrast, the C-terminus of ISD downregulates the pro-inflammatory response through the reduction of NF-kB and NFAT activities. The data also show that EBOV GP increases the adhesion of monocytes to endothelial cells, and the effect is inhibited by the ISD C-terminus. Moreover, the data demonstrate that the immunomodulating effects of ISD are mediated not only by the virus-associated GP but also by the shed GP, which is abundant in the medium. Pathogenesis of the disease caused by EBOV is characterized by hyperinflammation and some features of immunosuppression, which could in part be affected by the complex effects of the ISD. These data indicate that targeting the ISD may be considered for the development of treatments for the disease caused by EBOV.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0227825"},"PeriodicalIF":4.7000,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Distinct immune properties of the N- and C-termini of the immunosuppressive domain of Ebola virus glycoprotein.\",\"authors\":\"Mathieu Iampietro, Sivakumar Periasamy, Philipp A Ilinykh, Yuan Qiu, Yakun Liu, Abhinit Nagar, Bin Gong, Alexander Bukreyev\",\"doi\":\"10.1128/mbio.02278-25\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Ebola virus (EBOV) causes a severe human disease with high lethality. Pathogenesis of EBOV disease is characterized by a paradoxical combination of hyperinflammation and immunosuppression. EBOV has a single envelope glycoprotein (GP), which is a type I transmembrane protein with strong immunomodulatory effects. GP contains a conserved immunosuppressive domain (ISD) with a high similarity to ISDs of envelope proteins retroviruses. To investigate the effects of ISD, a set of 17 EBOV viral-like particle (VLP) constructs containing the entire EBOV nucleoprotein, VP40, and GP with single alanine or glycine substitutions in each position of ISD was generated and tested in human peripheral blood mononuclear cells (PBMCs). Wild-type VLPs induced inflammatory responses; however, when added to pre-stimulated cells, they reduced inflammation, thus exerting immunosuppressive properties. Substitution of lysine at ISD position 5 (Lys-5) increased anti-inflammatory properties by reducing proliferative responses of VLPs and also reducing nuclear factor of activated T-cells 1 (NFAT1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. In contrast, substitution of tryptophan at position 14 (Trp-14) increased both the pro-inflammatory and the proliferative responses and the adhesion of VLP-infected human monocytes to microvascular endothelial cells. Thus, the ISD N- and C-termini have pro- and anti-inflammatory properties, respectively, suggesting their unique implications in the EBOV pathogenesis. Furthermore, the immunomodulating effects of ISD were also mediated by shed GP, which is abundant in the medium. These data may be useful for the development of treatments for diseases caused by EBOV by targeting the ISD.IMPORTANCEOur data suggest that the ISD N-terminus plays a role in activating immune cells and pro-inflammatory response. In contrast, the C-terminus of ISD downregulates the pro-inflammatory response through the reduction of NF-kB and NFAT activities. The data also show that EBOV GP increases the adhesion of monocytes to endothelial cells, and the effect is inhibited by the ISD C-terminus. Moreover, the data demonstrate that the immunomodulating effects of ISD are mediated not only by the virus-associated GP but also by the shed GP, which is abundant in the medium. Pathogenesis of the disease caused by EBOV is characterized by hyperinflammation and some features of immunosuppression, which could in part be affected by the complex effects of the ISD. These data indicate that targeting the ISD may be considered for the development of treatments for the disease caused by EBOV.</p>\",\"PeriodicalId\":18315,\"journal\":{\"name\":\"mBio\",\"volume\":\" \",\"pages\":\"e0227825\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-10-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"mBio\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1128/mbio.02278-25\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"mBio","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1128/mbio.02278-25","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

埃博拉病毒(EBOV)是一种具有高致死率的严重人类疾病。EBOV病的发病机制以过度炎症和免疫抑制的矛盾结合为特征。EBOV具有单包膜糖蛋白(GP),这是一种具有强免疫调节作用的I型跨膜蛋白。GP含有一个保守的免疫抑制结构域(ISD),与逆转录病毒包膜蛋白的ISD高度相似。为了研究ISD的作用,制备了17个EBOV病毒样颗粒(VLP),其中包含EBOV整个核蛋白、VP40和GP, ISD的每个位置都有单个丙氨酸或甘氨酸取代,并在人外周血单个核细胞(PBMCs)中进行了测试。野生型VLPs诱导炎症反应;然而,当添加到预刺激的细胞中时,它们可以减少炎症,从而发挥免疫抑制特性。ISD位置5赖氨酸的替代(Lys-5)通过降低VLPs的增殖反应和降低活化t细胞的核因子1 (NFAT1)和活化B细胞的核因子kappa-轻链增强子(NF-κB)的活化来增加抗炎特性。相反,在位置14替换色氨酸(Trp-14)增加了促炎和增殖反应以及vlp感染的人单核细胞对微血管内皮细胞的粘附。因此,ISD N端和c端分别具有促炎和抗炎特性,表明它们在EBOV发病机制中具有独特的意义。此外,ISD的免疫调节作用也是由培养液中丰富的棚GP介导的。这些数据可能有助于开发针对ISD的EBOV引起的疾病的治疗方法。我们的数据表明,ISD n端在激活免疫细胞和促炎反应中起作用。相反,ISD的c端通过降低NF-kB和NFAT活性下调促炎反应。数据还显示,EBOV GP增加了单核细胞对内皮细胞的粘附,这种作用被ISD c端抑制。此外,这些数据表明,ISD的免疫调节作用不仅是由病毒相关的GP介导的,而且还由培养液中丰富的棚状GP介导。由EBOV引起的疾病的发病机制以过度炎症和免疫抑制为特征,这可能部分受到ISD的复杂作用的影响。这些数据表明,在开发EBOV引起的疾病的治疗方法时,可以考虑以ISD为靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Distinct immune properties of the N- and C-termini of the immunosuppressive domain of Ebola virus glycoprotein.

Ebola virus (EBOV) causes a severe human disease with high lethality. Pathogenesis of EBOV disease is characterized by a paradoxical combination of hyperinflammation and immunosuppression. EBOV has a single envelope glycoprotein (GP), which is a type I transmembrane protein with strong immunomodulatory effects. GP contains a conserved immunosuppressive domain (ISD) with a high similarity to ISDs of envelope proteins retroviruses. To investigate the effects of ISD, a set of 17 EBOV viral-like particle (VLP) constructs containing the entire EBOV nucleoprotein, VP40, and GP with single alanine or glycine substitutions in each position of ISD was generated and tested in human peripheral blood mononuclear cells (PBMCs). Wild-type VLPs induced inflammatory responses; however, when added to pre-stimulated cells, they reduced inflammation, thus exerting immunosuppressive properties. Substitution of lysine at ISD position 5 (Lys-5) increased anti-inflammatory properties by reducing proliferative responses of VLPs and also reducing nuclear factor of activated T-cells 1 (NFAT1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. In contrast, substitution of tryptophan at position 14 (Trp-14) increased both the pro-inflammatory and the proliferative responses and the adhesion of VLP-infected human monocytes to microvascular endothelial cells. Thus, the ISD N- and C-termini have pro- and anti-inflammatory properties, respectively, suggesting their unique implications in the EBOV pathogenesis. Furthermore, the immunomodulating effects of ISD were also mediated by shed GP, which is abundant in the medium. These data may be useful for the development of treatments for diseases caused by EBOV by targeting the ISD.IMPORTANCEOur data suggest that the ISD N-terminus plays a role in activating immune cells and pro-inflammatory response. In contrast, the C-terminus of ISD downregulates the pro-inflammatory response through the reduction of NF-kB and NFAT activities. The data also show that EBOV GP increases the adhesion of monocytes to endothelial cells, and the effect is inhibited by the ISD C-terminus. Moreover, the data demonstrate that the immunomodulating effects of ISD are mediated not only by the virus-associated GP but also by the shed GP, which is abundant in the medium. Pathogenesis of the disease caused by EBOV is characterized by hyperinflammation and some features of immunosuppression, which could in part be affected by the complex effects of the ISD. These data indicate that targeting the ISD may be considered for the development of treatments for the disease caused by EBOV.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
mBio
mBio MICROBIOLOGY-
CiteScore
10.50
自引率
3.10%
发文量
762
审稿时长
1 months
期刊介绍: mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信