Polypyrimidine Tract-Binding #Protein Regulates #Enterovirus 71 #Translation Through Interaction with the Internal #Ribosomal Entry Site (Virol Sin., abstract)

[Source: Virologica Sinica, full page: (LINK). Abstract, edited.]

Polypyrimidine Tract-Binding Protein Regulates Enterovirus 71 Translation Through Interaction with the Internal Ribosomal Entry Site

Authors and affiliations: Juemin Xi 1, Fei Ye 2, Guanzhou Wang 2, Wei Han 2, Zhizhong Wei 2, Bin Yin 2, Jiangang Yuan 2, Boqin Qiang 2, Xiaozhong Peng 1, 2

1 Institute of Medical Biology, Chinese Academy of Medical Sciences, and Peking Union Medical College, Kunming, China; 2 The State Key Laboratory of Medical Molecular Biology, Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Open Access / RESEARCH ARTICLE / First Online: 22 February 2019

 

Abstract

Enterovirus 71 (EV71), a major causative agent of hand, foot, and mouth disease, has caused periodic infection outbreaks in children in the Asia–Pacific region. In order to describe the largely unknown life cycle of EV71, the molecular basis of its virus-host interactions must first be determined. The 5′ untranslated region of EV71 contains a cloverleaf-like structure and internal ribosomal entry site (IRES), which play an important role in transcription and translation of viral protein. We found that polypyrimidine tract-binding protein 1 (PTB) bound to the IRES of EV71. RNA recognition motifs 1 and 2 of PTB were responsible for its binding to the EV71 IRES. Moreover, PTB protein was shuttled from nucleus to cytoplasm after EV71 infection. Additionally, IRES activity and viral protein production were inhibited by PTB knockdown. These results suggest that PTB interacts with the EV71 IRES, and positively regulates viral protein translation.

Keywords: EV71 – IRES – PTB – Translation

 

Electronic supplementary material

The online version of this article ( https://doi.org/10.1007/s12250-019-00089-1) contains supplementary material, which is available to authorized users.

Juemin Xi and Fei Ye contributed equally to this work.

Keywords: EV-71; HFMD.

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Recent #Progress on Functional #Genomics Research of #Enterovirus 71 (Virol Sin., abstract)

[Source: Virologica Sinica, full page: (LINK). Abstract, edited.]

Recent Progress on Functional Genomics Research of Enterovirus 71

Authors: Huiqiang Wang, Yuhuan Li

First Online: 14 December 2018

 

Abstract

Enterovirus 71 (EV71) is one of the main pathogens that causes hand-foot-and-mouth disease (HFMD). HFMD caused by EV71 infection is mostly self-limited; however, some infections can cause severe neurological diseases, such as aseptic meningitis, brain stem encephalitis, and even death. There are still no effective clinical drugs used for the prevention and treatment of HFMD. Studying EV71 protein function is essential for elucidating the EV71 replication process and developing anti-EV71 drugs and vaccines. In this review, we summarized the recent progress in the studies of EV71 non-coding regions (5′ UTR and 3′ UTR) and all structural and nonstructural proteins, especially the key motifs involving in viral infection, replication, and immune regulation. This review will promote our understanding of EV71 virus replication and pathogenesis, and will facilitate the development of novel drugs or vaccines to treat EV71.

Keywords: Enterovirus 71 (EV71) – Functional genomics – Structural protein – Nonstructural protein – Viral protein function

 

Acknowledgements

The work was supported by the National Natural Science Foundation of China (Grant 81503118) and CAMS Initiative for Innovative Medicine (CAMS-I2 M-1-010); The National Science and Technology Major Project of the Ministry of Science and Technology of China (2018ZX09711003-005-004).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Animal and Human Rights Statement

The authors declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

Keywords: EV-71; Enterovirus; HFMD; Genetics.

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#Evolution and spatio-temporal #dynamics of #Enterovirus A71 subgenogroups in #Vietnam (J Infect Dis., abstract)

[Source: The Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Evolution and spatio-temporal dynamics of Enterovirus A71 subgenogroups in Vietnam

Nguyen Thi Thanh, Celeste Donato, Vu Thi Huyen Trang, Nguyen Trung Kien, Phạm Mai Thuy Trang, Tran Quoc Khanh, Dang Thi Nguyet, Hoang Quoc Cuong, Phan Trong Lan, Vu Thi Que Huong, H Rogier van Doorn, Vijaykrishna Dhanasekaran

#Corresponding author: Vijaykrishna Dhanasekaran vijay.dhanasekaran@monash.edu Department of Microbiology 19 Innovation Drive Monash University Clayton 3800 Phone: +613 9905 5415 Fax: +613 9902 9222

The Journal of Infectious Diseases, jix500, https://doi.org/10.1093/infdis/jix500

Published: 23 September 2017 – Received: 28 February 2017

Citation: Nguyen Thi Thanh Thao, Celeste Donato, Vu Thi Huyen Trang, Nguyen Trung Kien, Phạm Mai Thuy Trang, Tran Quoc Khanh, Dang Thi Nguyet, October Sessions, Hoang Quoc Cuong, Phan Trong Lan, Vu Thi Que Huong, H Rogier van Doorn, Vijaykrishna Dhanasekaran; Evolution and spatio-temporal dynamics of Enterovirus A71 subgenogroups in Vietnam, The Journal of Infectious Diseases, , jix500, https://doi.org/10.1093/infdis/jix500

© 2017 Oxford University Press

 

Abstract

Background

Enterovirus A71 (EV-A71) is the major cause of severe hand, foot and mouth disease and viral encephalitis in children across the Asia-Pacific region, including in Vietnam which has experienced a high burden of disease in recent years. Multiple subgenogroups (C1, C4, C5 and B5) concurrently circulate in the region with a large variation in epidemic severity. The relative differences in their evolution and epidemiology were examined within Vietnam and globally.

Methods

A total of 752 VP1 gene sequences were analysed (413 generated in this study combined with 339 obtained from GenBank), collected from patients in 36 provinces in Vietnam during 2003–2013 along with epidemiological metadata. Globally representative VP1 gene datasets of subgenogroups were used to co-estimate time-resolved phylogenies and relative genetic diversity to infer virus origins and regional transmission network.

Results

Despite frequent virus migration between countries, the highest genetic diversity of individual subgenogroups was maintained independently for several years in specific Asian countries representing genogroup-specific sources of EV-A71 diversity.

Conclusion

This study highlights a persistent transmission network of EV-A71, with specific Asian countries seeding other countries in the region and beyond, emphasising the need for improved EV-A71 surveillance and detailed genetic and antigenic characterisation.

Enterovirus A71, Vietnam, Hand Foot and Mouth Disease, Phylogenetics

Topic: metadata – enterovirus – epidemiology – hand-foot-and-mouth disease – asia – child – cost of illness – viral encephalitis – genes – phylogeny – vietnam – genetics – viruses – persistence – epidemic – surveillance, medical – asian – absolute risk reduction – genbank – datasets

Issue Section: Major Article

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Keywords: EV-71; HFMD; Asian Region; Vietnam.

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293tExosome-mediated miR-146a transfer suppresses type I #interferon response and facilitates #EV71 #infection (PLoS Pathogens, abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

293tExosome-mediated miR-146a transfer suppresses type I interferon response and facilitates EV71 infection

Yuxuan Fu, Li Zhang, Fang Zhang, Ting Tang, Qi Zhou, Chunhong Feng, Yu Jin, Zhiwei Wu

Published: September 14, 2017 / DOI: https://doi.org/10.1371/journal.ppat.1006611 /  This is an uncorrected proof.

 

Abstract

Exosomes can transfer genetic materials between cells. Their roles in viral infections are beginning to be appreciated. Researches have shown that exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modulate recipient’s cellular response and result in productive infection of the recipient host. Here, we showed that EV71 infection resulted in upregulated exosome secretion and differential packaging of the viral genomic RNA and miR-146a into exosomes. We provided evidence showing that miR-146a was preferentially enriched in exosomes while the viral RNA was not in infected cells. Moreover, the exosomes contained replication-competent EV71 RNA in complex with miR-146a, Ago2, and GW182 and could mediate EV71 transmission independent of virus-specific receptor. The exosomal viral RNA could be transferred to and replicate in a new target cell while the exosomal miR-146a suppressed type I interferon response in the target cell, thus facilitating the viral replication. Additionally, we found that the IFN-stimulated gene factors (ISGs), BST-2/tetherin, were involved in regulating EV71-induced upregulation of exosome secretion. Importantly, in vivo study showed that exosomal viral RNA exhibited differential tissue accumulation as compared to the free virus particles. Together, our findings provide evidence that exosomes secreted by EV71-infected cells selectively packaged high level miR-146a that can be functionally transferred to and facilitate exosomal EV71 RNA to replicate in the recipient cells by suppressing type I interferon response.

 

Author summary

Exosomes are small membrane-encapsulated vesicles that secrete into the extracellular environment. Various proteins and RNA molecules have been identified in exosomes whose content reflects the physiological or pathological state of the host cells. Researches have shown that exosomes released from virus-infected cells contain a variety of viral and host cellular factors that are able to modulate recipient’s cellular responses and result in productive infection of the recipient host. Here, we showed that Enterovirus 71 (EV71), a non-enveloped, single-strand positive sense RNA virus that belongs to the family Picornaviridae and is a major etiologic agent of hand-foot and-mouth disease (HFMD), could stimulate exosome secretion and differential packaging of the viral genomic RNA and miR-146a into exosomes. The exosomal viral RNA could be transferred to and replicate in a new target cell while the exosomal miR-146a suppressed type I interferon response in the target cell, thus facilitating the viral replication. Importantly, in vivo study showed that exosomal viral RNA exhibited differential tissue accumulation as compared to the free virus particles. We postulate that the preferential packaging of miRNA-146a into exosome is a viral strategy of suppressing host innate immunity upon infection and the exosomal EV 71 RNA may play an important pathogenic role in the infection.

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Citation: Fu Y, Zhang L, Zhang F, Tang T, Zhou Q, Feng C, et al. (2017) 293tExosome-mediated miR-146a transfer suppresses type I interferon response and facilitates EV71 infection. PLoS Pathog 13(9): e1006611. https://doi.org/10.1371/journal.ppat.1006611

Editor: Carolyn B. Coyne, University of Pittsburgh, UNITED STATES

Received: May 4, 2017; Accepted: August 28, 2017; Published: September 14, 2017

Copyright: © 2017 Fu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This study was supported by The National Key Research and Development Program of China (2016YFC1201000), Nature Science Foundation of Jiangsu Province (BY2015069-02) and National Nature Science Foundation of China (81672020). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: EV-71; Interferons.

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Cost-effectiveness of a national #enterovirus 71 #vaccination program in #China (PLoS Negl Trop Dis., abstract)

[Source: PLoS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Cost-effectiveness of a national enterovirus 71 vaccination program in China

Wenjun Wang , Jianwen Song , Jingjing Wang , Yaping Li, Huiling Deng, Mei Li, Ning Gao, Song Zhai, Shuangsuo Dang , Xin Zhang, Xiaoli Jia

Published: September 11, 2017 / DOI: https://doi.org/10.1371/journal.pntd.0005899 / This is an uncorrected proof.

 

Abstract

Background and aims

Enterovirus 71 (EV71) has caused great morbidity, mortality, and use of health service in children younger than five years in China. Vaccines against EV71 have been proved effective and safe by recent phase 3 trials and are now available in China. The purpose of this study was to evaluate the health impact and cost-effectiveness of a national EV71 vaccination program in China.

Methods

Using Microsoft Excel, a decision model was built to calculate the net clinical and economic outcomes of EV71 vaccination compared with no EV71 vaccination in a birth cohort of 1,000,000 Chinese children followed for five years. Model parameters came from published epidemiology, clinical and cost data.

Results

In the base-case, vaccination would annually avert 37,872 cases of hand, foot and mouth disease (HFMD), 2,629 herpangina cases, 72,900 outpatient visits, 6,363 admissions to hospital, 29 deaths, and 945 disability adjusted life years. The break-even price of the vaccine was $5.2/dose. When the price was less than $8.3 or $14.6/dose, the vaccination program would be highly cost-effective or cost-effective, respectively (incremental cost-effectiveness ratio less than or between one to three times China GDP per capita, respectively). In one-way sensitivity analyses, the HFMD incidence was the only influential parameter at the price of $5/dose.

Conclusions

Within the price range of current routine vaccines paid by the government, a national EV71 vaccination program would be cost-saving or highly cost-effective to prevent EV71 related morbidity, mortality, and use of health service among children younger than five years in China. Policy makers should consider including EV71 vaccination as part of China’s routine childhood immunization schedule.

 

Author summary

Enterovirus 71 (EV71) has caused great morbidity, mortality, and use of health service in children younger than five years in China. Recently, effective and safe vaccines against EV71 have been approved. Whether EV71 vaccination should be included as part of China’s routine childhood immunization schedule is unknown. In this study, we built a decision model to evaluate the health impact and cost-effectiveness of a national EV71 vaccination program in China. We find that vaccination would annually avert 567,500 cases of hand, foot and mouth disease (HFMD), 40,000 herpangina cases, 1,093,500 outpatient visits, 95,500 admissions to hospital, 435 deaths, and 14,000 disability adjusted life years based on the current Chinese birth cohort size. The break-even price of the vaccine was $5.2/dose. Within the price range of current routine vaccines paid by the government, a national EV71 vaccination program would be cost-saving or highly cost-effective. Policy makers should consider including EV71 vaccination as part of China’s routine childhood immunization schedule.

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Citation: Wang W, Song J, Wang J, Li Y, Deng H, Li M, et al. (2017) Cost-effectiveness of a national enterovirus 71 vaccination program in China. PLoS Negl Trop Dis 11(9): e0005899. https://doi.org/10.1371/journal.pntd.0005899

Editor: Isaac Chun-Hai Fung, Georgia Southern University Jiann-Ping Hsu College of Public Health, UNITED STATES

Received: April 5, 2017; Accepted: August 23, 2017; Published: September 11, 2017

Copyright: © 2017 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Keywords: EV-71; Vaccines; China.

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#EV71 inhibits #pyroptosis through cleavage of GSDMD (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Enterovirus 71 inhibits pyroptosis through cleavage of GSDMD

Xiaobo Lei1, Zhenzhen Zhang1, Xia Xiao1, Jianli Qi1, Bin He2* and Jianwei Wang1,3*

Author Affiliations: 1 MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China; 2 Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, IL 60612, USA; 3 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, 310003, Zhejiang Province, China.

 

ABSTRACT

Enterovirus 71 (EV71) can cause hand, foot, and mouth disease (HFMD) in young children. Severe infection with EV71 can lead to neurological complications and even death. However, the molecular basis of viral pathogenesis remain poorly understand. Here, we report that EV71 induces degradation of GSDMD, an essential component of pyroptosis. Remarkably, the viral protease 3C directly targets GSDMD and induces its cleavage, which is dependent on the protease activity. Further analyses show that the Q193-G194 pair within GSDMD is the cleavage site of 3C. This cleavage produces a shorter N-terminal fragment spanning amino acids 1-193. However, unlike the N-terminal fragment produced by casaspe-1 cleavage, this fragment fails to trigger cell death or inhibits EV71 replication. Importantly, T239D or F240D substitution abrogates the activity of GSDMD composed of amino acids 1-275. This is correlated with the lack of pyroptosis or inhibition of viral replication. These results reveal a previously unrecognized strategy for EV71 to evade the antiviral response.

 

IMPORTANCE

Recently, it has been reported that GSDMD plays a critical role in regulating lipopolysaccharide and NLRP3-mediated IL-1β secretion. In this process, the N-terminal domain p30 released from GSDMD acts as an effector in cell pyroptosis. We show that EV71 infection down-regulates GSDMD. EV71 3C cleaves GSDMD at the Q193-G194 pair, resulting in a truncated N—terminal fragment disrupted for inducing cell pyroptosis. Notably, the 1-275aa fragment (p30) inhibits EV71 replication whereas the 1-193aa fragment does not. These results reveal a new strategy for EV71 to evade the antiviral response.

 

FOOTNOTES

*Correspondence and requests for materials should be addressed to J.W. (email: wangjw28@163.com) or B.H. (email: tshuo@uic.edu)

Copyright © 2017 American Society for Microbiology. All Rights Reserved.

Keywords: EV71; HFMD.

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UGGT1 enhances #enterovirus 71 #pathogenicity by promoting viral RNA synthesis and viral replication (PLoS Pathogens, abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE

UGGT1 enhances enterovirus 71 pathogenicity by promoting viral RNA synthesis and viral replication

Peng-Nien Huang, Jia-Rong Jheng, Jamie J. Arnold, Jen-Ren Wang, Craig E. Cameron, Shin-Ru Shih

Published: May 17, 2017 / https://doi.org/10.1371/journal.ppat.1006375

 

Abstract

Positive-strand RNA virus infections can induce the stress-related unfolded protein response (UPR) in host cells. This study found that enterovirus A71 (EVA71) utilizes host UDP-glucose glycoprotein glucosyltransferase 1 (UGGT1), a key endoplasmic reticulum protein (ER) involved in UPR, to enhance viral replication and virulence. EVA71 forms replication complexes (RCs) on cellular membranes that contain a mix of host and viral proteins to facilitate viral replication, but the components and processes involved in the assembly and function of RCs are not fully understood. Using EVA71 as a model, this study found that host UGGT1 and viral 3D polymerase co-precipitate along with other factors on membranous replication complexes to enhance viral replication. Increased UGGT1 levels elevated viral growth rates, while viral pathogenicity was observed to be lower in heterozygous knockout mice (Uggt1 +/- mice). These findings provide important insight on the role of UPR and host UGGT1 in regulating RNA virus replication and pathogenicity.

 

Author summary

Positive-strand RNA viruses are adept at hijacking host cell machinery to promote viral propagation, including the formation of RCs containing viral and host proteins on intracellular membranes to facilitate virion assembly and avoid detection by host defense mechanisms. However, the processes by which RCs are assembled, as well as the host proteins involved, have not been fully elucidated as yet. Here, we show that the endoplasmic reticulum (ER) protein UGGT1, a key regulator of the UPR host defense mechanism, co-precipitates with the 3D polymerase of EVA71 to facilitate RC formation, enhance viral RNA synthesis, and promote viral replication. Knockout of Uggt1 reduced viral pathogenicity in animal studies. These findings highlight the role to which viruses can hijack key host proteins to promote viral replication, and may serve as the basis for the development of novel anti-viral strategies.

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Citation: Huang P-N, Jheng J-R, Arnold JJ, Wang J-R, Cameron CE, Shih S-R (2017) UGGT1 enhances enterovirus 71 pathogenicity by promoting viral RNA synthesis and viral replication. PLoS Pathog 13(5): e1006375. https://doi.org/10.1371/journal.ppat.1006375

Editor: Bert L. Semler, University of California, Irvine, UNITED STATES

Received: January 24, 2017; Accepted: April 24, 2017; Published: May 17, 2017

Copyright: © 2017 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This work was supported by the Taiwan Ministry of Science and Technology (https://www.most.gov.tw/) grant NSC-101-2325-B-182-015 awarded to SRS; and Chang Gung Memorial Hospital (https://www.cgmh.org.tw/eng2002/index.asp) grants CMRPD1A0671, CMRPD1A0672, CMRPD1A0673, CMRPD1E0401, CMRPD1E0402, and CMRPD1E0403 awarded to SRS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Enterovirus; EV-71.

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