scholarly journals Foot-and-mouth disease virus VP1 target the MAVS to inhibit type-I interferon signaling and VP1 E83K mutation results in virus attenuation

2020 ◽  
Vol 16 (11) ◽  
pp. e1009057
Author(s):  
Pathum Ekanayaka ◽  
Seo-Yong Lee ◽  
Thilina U. B. Herath ◽  
Jae-Hoon Kim ◽  
Tae-Hwan Kim ◽  
...  
Keyword(s):  
Cell Culture ◽  
Disease Virus ◽  
Critical Role ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Type I ◽  
Wild Type ◽  
Humoral Immune ◽  
Mouth Disease Virus ◽  
Foot And Mouth

VP1, a pivotal capsid protein encoded by the foot-and-mouth disease virus (FMDV), plays an important role in receptor-mediated attachment and humoral immune responses. Previous studies show that amino acid changes in the VP1 protein of cell culture-adapted strains of FMDV alter the properties of the virus. In addition, FMDV VP1 modulates host IFN signal transduction. Here, we examined the ability of cell culture-adapted FMDV VP1(83K) and wild-type FMDV VP1(83E) to evade host immunity by blocking mitochondrial antiviral signaling protein (MAVS)/TNF Receptor Associated Factor 3 (TRAF3) mediated cellular innate responses. Wild-type FMDV VP1(83E) interacted specifically with C-terminal TRAF3-binding site within MAVS and this interaction inhibited binding of TRAF3 to MAVS, thereby suppressing interferon-mediated responses. This was not observed for cell culture-adapted FMDV VP1(83K). Finally, chimeric FMDV harboring VP1(83K) showed very low pathogenicity in pigs. Collectively, these data highlight a critical role of VP1 with respect to suppression of type-I IFN pathway and attenuation of FMDV by the E83K mutation in VP1.

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.

Porcine Type I Interferon Rapidly Protects Swine Against Challenge with Multiple Serotypes of Foot-and-Mouth Disease Virus

2011 ◽  
Vol 31 (2) ◽  
pp. 227-236 ◽  
Author(s):  
Camila C.A. Dias ◽  
Mauro P. Moraes ◽  
Fayna Diaz-San Segundo ◽  
Teresa de los Santos ◽  
Marvin J. Grubman
Keyword(s):  
Disease Virus ◽  
Type I Interferon ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Type I ◽  
Mouth Disease Virus ◽  
Foot And Mouth

scholarly journals Domain disruptions of individual 3B proteins of foot-and-mouth disease virus do not alter growth in cell culture or virulence in cattle

Virology ◽  
2010 ◽  
Vol 405 (1) ◽  
pp. 149-156 ◽  
Author(s):  
Juan M. Pacheco ◽  
Maria E. Piccone ◽  
Elizabeth Rieder ◽  
Steven J. Pauszek ◽  
Manuel V. Borca ◽  
...  
Keyword(s):  
Cell Culture ◽  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Mouth Disease Virus ◽  
Foot And Mouth

scholarly journals Inhibition of MAVS Aggregation-Mediated Type-I Interferon Signaling by Foot-and-Mouth Disease Virus VP3

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1776
Author(s):  
Pathum Ekanayaka ◽  
Byeong-Hoon Lee ◽  
Asela Weerawardhana ◽  
Kiramage Chathuranga ◽  
Jong-Hyeon Park ◽  
...  
Keyword(s):  
Disease Virus ◽  
Virus Assembly ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Clear Understanding ◽  
Type I ◽  
Type I Ifn ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Tm Domain

As a structural protein of the Foot-and-mouth disease virus (FMDV), VP3 plays a vital role in virus assembly and inhibiting the interferon (IFN) signal transduction to promote FMDV replication. Previous studies demonstrated that FMDV VP3 blocks the type-I IFN response by inhibiting the mRNA expression of the mitochondrial antiviral-signaling protein (MAVS); however, the underlying mechanism is poorly understood. Here, we describe the specificity of FMDV VP3 interaction with the transmembrane (TM) domain of MAVS as FMDV driven type-I IFN inhibitory mechanism for its effective replication. The TM domain of MAVS governs the mitochondria localization of MAVS, and it is a key factor in type-I IFN signaling transduction via MAVS aggregation. Thereby, the interaction of FMDV VP3 with the TM domain of MAVS leads to the inhibition of MAVS mitochondria localization, self-association, and aggregation, resulting in the suppression of type-I IFN response. Collectively, these results provide a clear understanding of a key molecular mechanism used by the FMDV VP3 for the suppression of IFN responses via targeting MAVS.

scholarly journals Evaluation of Genetically Engineered Derivatives of a Chinese Strain of Foot-and-Mouth Disease Virus Reveals a Novel Cell-Binding Site Which Functions in Cell Culture and in Animals

2003 ◽  
Vol 77 (5) ◽  
pp. 3269-3280 ◽  
Author(s):  
Qizu Zhao ◽  
Juan M. Pacheco ◽  
Peter W. Mason
Keyword(s):  
Cell Culture ◽  
Cell Surface ◽  
Host Range ◽  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Cell Binding ◽  
Coding Regions ◽  
Mouth Disease Virus ◽  
Foot And Mouth

ABSTRACT Adaptation of field isolates of foot-and-mouth disease virus (FMDV) to grow in cells in culture can result in changes in viral properties that include acquisition of the ability to bind to cell surface heparan sulfate (HS). After 13 passages on BHK cells to produce a vaccine, a Cathay topotype isolate of FMDV serotype O from China (O/CHA/90) extended its cell culture host range and bound to heparin-Sepharose, although it did not require cell surface HS as a receptor molecule. To understand these phenomena, we constructed chimeric viruses by using a type A12 infectious cDNA and the capsid protein-coding regions of O/CHA/90 and its cell culture-adapted derivative (vac-O/CHA/90). Using a set of viruses derived from these chimeras by exchanging portions of the capsid-coding regions, we discovered that a group of amino acid residues that surround the fivefold axis of the icosahedral virion determine host range in cell culture and influence pathogenicity in pigs. These residues included aromatic amino acids at positions 108 and 174 and positively charged residues at positions 83 and 172 in protein 1D. To test if these residues participated in non-integrin-dependent cell binding, the integrin-binding RGD sequence in protein 1D was changed to KGE in two different chimeras. Evaluation of these KGE viruses indicated that growth in cell culture was not dependent on HS. One of these viruses was tested in pigs, where it produced a mild disease and maintained its KGE sequence. These results are discussed in terms of receptor utilization and pathogenesis of this important pathogen.

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