scholarly journals Inhibition of foot-and-mouth disease virus replication in vitro and in vivo by small interfering RNA

2008 ◽  
Vol 5 (1) ◽  
pp. 86 ◽  
Author(s):  
Wang Pengyan ◽  
Ren Yan ◽  
Guo Zhiru ◽  
Chen Chuangfu
Keyword(s):  
Disease Virus ◽  
Virus Replication ◽  
Small Interfering Rna ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Interfering Rna

scholarly journals The DDX23 Negatively Regulates Translation and Replication of Foot-and-Mouth Disease Virus and Is Degraded by 3C Proteinase

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1348
Author(s):  
Sahibzada Waheed Abdullah ◽  
Shichong Han ◽  
Jin’en Wu ◽  
Yun Zhang ◽  
Manyuan Bai ◽  
...  
Keyword(s):  
Disease Virus ◽  
Small Interfering Rna ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Dependent Manner ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Rna Knockdown ◽  
Interfering Rna ◽  
Fmdv Replication

DEAD-box helicase 23 (DDX23) is a host nuclear helicase, which is a part of the spliceosomal complex and involved in pre-mRNA splicing. To investigate whether DDX23, an internal ribosomal entry sites transacting factor (ITAF) affects foot-and-mouth disease virus (FMDV) replication and translation through internal ribosome entry site (IRES)-dependent manner. For this, we utilized a pull-down assay, Western blotting, quantitative real-time PCR, confocal microscopy, overexpression and small interfering RNA knockdown, as well as the median tissue culture infective dose. Our findings showed that FMDV infection inhibited DDX23 expression and the overexpression of DDX23 reduced viral replication, however, CRISPR Cas9 knockout/small interfering RNA knockdown increased FMDV replication. FMDV IRES domain III and IV interacted with DDX23, whereas DDX23 interacted with FMDV 3C proteinase and significantly degraded. The enzymatic activity of FMDV 3C proteinase degraded DDX23, whereas FMDV degraded DDX23 via the lysosomal pathway. Additionally, IRES-driven translation was suppressed in DDX23-overexpressing cells, and was enhanced in DDX23 knocked down. Collectively, our results demonstrated that DDX23 negatively affects FMDV IRES-dependent translation, which could be a useful target for the design of antiviral drugs.

scholarly journals Impairment of the DeISGylation Activity of Foot-and-Mouth Disease Virus Lpro Causes Attenuation In Vitro and In Vivo

2020 ◽  
Vol 94 (13) ◽  
Author(s):  
Gisselle N. Medina ◽  
Paul Azzinaro ◽  
Elizabeth Ramirez-Medina ◽  
Joseph Gutkoska ◽  
Ying Fang ◽  
...  
Keyword(s):  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Type I ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Infected Cells ◽  
Viral Attenuation

ABSTRACT Foot-and-mouth disease virus (FMDV) leader proteinase (Lpro) affects several pathways of the host innate immune response. Previous studies in bovine cells demonstrated that deletions (leaderless [LLV]) or point mutations in Lpro result in increased expression of interferon (IFN) and IFN-stimulated genes (ISGs), including, among others, the ubiquitin-like protein modifier ISG15 and the ubiquitin specific peptidase USP18. In addition to its conventional papain-like protease activity, Lpro acts as a deubiquitinase (DUB) and deISGylase. In this study, we identified a conserved residue in Lpro that is involved in its interaction with ISG15. Mutation W105A rendered Escherichia coli-expressed Lpro unable to cleave the synthetic substrate pro-ISG15 while preserving cellular eIF4G cleavage. Interestingly, mutant FMDV W105A was viable. Overexpression of ISG15 and the ISGylation machinery in porcine cells resulted in moderate inhibition of FMDV replication, along with a decrease of the overall state of ISGylation in wild-type (WT)-infected cells. In contrast, reduced deISGylation was observed upon infection with W105A and leaderless virus. Reduction in the levels of deubiquitination was also observed in cells infected with the FMDV LproW105A mutant. Surprisingly, similarly to WT, infection with W105A inhibited IFN/ISG expression despite displaying an attenuated phenotype in vivo in mice. Altogether, our studies indicate that abolishing/reducing the deISGylase/DUB activity of Lpro causes viral attenuation independently of its ability to block the expression of IFN and ISG mRNA. Furthermore, our studies highlight the potential of ISG15 to be developed as a novel biotherapeutic molecule against FMD. IMPORTANCE In this study, we identified an aromatic hydrophobic residue in foot-and-mouth disease virus (FMDV) leader proteinase (Lpro) (W105) that is involved in the interaction with ISG15. Mutation in Lpro W105 (A12-LproW105A) resulted in reduced deISGylation in vitro and in porcine-infected cells. Impaired deISGylase activity correlated with viral attenuation in vitro and in vivo and did not affect the ability of Lpro to block expression of type I interferon (IFN) and other IFN-stimulated genes. Moreover, overexpression of ISG15 resulted in the reduction of FMDV viral titers. Thus, our study highlights the potential use of Lpro mutants with modified deISGylase activity for development of live attenuated vaccine candidates, and ISG15 as a novel biotherapeutic against FMD.

scholarly journals Genetic and Phenotypic Variation of Foot-and-Mouth Disease Virus during Serial Passages in a Natural Host

2007 ◽  
Vol 81 (20) ◽  
pp. 11341-11351 ◽  
Author(s):  
C. Carrillo ◽  
Z. Lu ◽  
M. V. Borca ◽  
A. Vagnozzi ◽  
G. F. Kutish ◽  
...  
Keyword(s):  
Disease Virus ◽  
Virus Replication ◽  
Cell Cultures ◽  
Rna Viruses ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Natural Host ◽  
Mouth Disease Virus

ABSTRACT Foot-and-mouth disease virus (FMDV), like other RNA viruses, exhibits high mutation rates during replication that have been suggested to be of adaptive value. However, even though genetic variation in RNA viruses and, more specifically, FMDV has been extensively examined during virus replication in a wide variety of in vitro cell cultures, very little is known regarding the generation and effects of genetic variability of virus replication in the natural host under experimental conditions and no genetic data are available regarding the effects of serial passage in natural hosts. Here, we present the results of 20 serial contact transmissions of the highly pathogenic, pig-adapted O Taiwan 97 (O Tw97) isolate of FMDV in swine. We examined the virus genomic consensus sequences for a total of 37 full-length viral genomes recovered from 20 in vivo passages. The characteristics and distributions of changes in the sequences during the series of pig infections were analyzed in comparison to the O Tw97 genomes recovered from serially infected BHK-21 cell cultures. Unexpectedly, a significant reduction of virulence upon pig passages was observed, and finally, interruption of the viral transmission chain occurred after the14th pig passage (T14). Virus was, however, isolated from the tonsils and nasal swabs of the asymptomatic T15 pigs at 26 days postcontact, consistent with a natural establishment of the carrier state previously described only for ruminants. Surprisingly, the region encoding the capsid protein VP1 (1D) did not show amino acid changes during in vivo passages. These data demonstrate that contact transmission of FMDV O Tw97 in pigs mimics the fitness loss induced by the bottleneck effect, which was previously observed by others during plaque-to-plaque FMDV passage in vitro, suggesting that unknown mechanisms of virulence recovery might be necessary during the evolution and perpetuation of FMDV in nature.

scholarly journals Role of RNA Structure and RNA Binding Activity of Foot-and-Mouth Disease Virus 3C Protein in VPg Uridylylation and Virus Replication

2006 ◽  
Vol 80 (19) ◽  
pp. 9865-9875 ◽  
Author(s):  
Arabinda Nayak ◽  
Ian G. Goodfellow ◽  
Kathryn E. Woolaway ◽  
James Birtley ◽  
Stephen Curry ◽  
...  
Keyword(s):  
Disease Virus ◽  
Virus Replication ◽  
Rna Structure ◽  
Rna Binding ◽  
Foot And Mouth Disease ◽  
Binding Activity ◽  
Mouth Disease ◽  
Mouth Disease Virus ◽  
Foot And Mouth

ABSTRACT The uridylylation of the VPg peptide primer is the first stage in the replication of picornavirus RNA. This process can be achieved in vitro using purified components, including 3B (VPg) with the RNA dependent RNA polymerase (3D pol ), the precursor 3CD, and an RNA template containing the cre/bus. We show that certain RNA sequences within the foot-and-mouth disease virus (FMDV) 5′ untranslated region but outside of the cre/bus can enhance VPg uridylylation activity. Furthermore, we have shown that the FMDV 3C protein alone can substitute for 3CD, albeit less efficiently. In addition, the VPg precursors, 3B33C and 3B1233C, can function as substrates for uridylylation in the absence of added 3C or 3CD. Residues within the FMDV 3C protein involved in interaction with the cre/bus RNA have been identified and are located on the face of the protein opposite from the catalytic site. These residues within 3C are also essential for VPg uridylylation activity and efficient virus replication.

scholarly journals Antiviral activity of brequinar against foot-and-mouth disease virus infection in vitro and in vivo

2019 ◽  
Vol 116 ◽  
pp. 108982 ◽  
Author(s):  
Shi-fang Li ◽  
Mei-jiao Gong ◽  
Yue-feng Sun ◽  
Jun-jun Shao ◽  
Yong-guang Zhang ◽  
...  
Keyword(s):  
Virus Infection ◽  
Antiviral Activity ◽  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Mouth Disease Virus ◽  
Foot And Mouth

An increased replication fidelity mutant of foot-and-mouth disease virus retains fitness in vitro and virulence in vivo

2013 ◽  
Vol 100 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Jianxiong Zeng ◽  
Haiwei Wang ◽  
Xiaochun Xie ◽  
Decheng Yang ◽  
Guohui Zhou ◽  
...  
Keyword(s):  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Replication Fidelity ◽  
Mouth Disease Virus ◽  
Foot And Mouth
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