MiR-4334-5p Facilitates Foot and Mouth Disease Virus Propagation by Suppressing Interferon Pathways via Direct Targeting ID1

Emerging evidence indicates that the host microRNAs (miRNAs) are important intracellular regulators and play pivotal roles in intricate host-pathogen interaction networks. In our previous studies, ssc-microRNA-4334-5p (miR-4334-5p) was identified as a differentially expressed miRNA in microarray-based miRNAs profiling experiment, but whether miR-4334-5p regulates foot and mouth disease virus (FMDV) propagation is less understood. Here, we demonstrated that miR-4334-5p expression level was up-regulated shortly after FMDV infection, transfection of miR-4334-5p mimics promoted, while inhibitor transfection suppressed FMDV replication correspondingly. Further bioinformatic analysis and experimental study suggested ID1 was the direct target of miR-4334-5p, suppressing FMDV replication by regulating interferon (IFN) pathways. These findings shed light on microRNAs-ID1-interferon axis in regulating FMDV replication.

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Lithium chloride inhibits early stages of foot-and-mouth disease virus (FMDV) replication in vitro

Journal of Medical Virology ◽

10.1002/jmv.24821 ◽

2017 ◽

Vol 89 (11) ◽

pp. 2041-2046 ◽

Cited By ~ 15

Author(s):

Fu-Rong Zhao ◽

Yin-Li Xie ◽

Ze-Zhong Liu ◽

Jun-Jun Shao ◽

Shi-Fang Li ◽

...

Keyword(s):

Disease Virus ◽

Lithium Chloride ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Early Stages ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Fmdv Replication

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

Viruses ◽

10.3390/v12121348 ◽

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.

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Basal Level p53 Suppresses Antiviral Immunity against Foot-and-Mouth Disease Virus

Viruses ◽

10.3390/v11080727 ◽

2019 ◽

Vol 11 (8) ◽

pp. 727

Author(s):

Zhang ◽

Chen ◽

Liu ◽

Qi ◽

Gao ◽

...

Keyword(s):

Innate Immunity ◽

Disease Virus ◽

Knockout Mice ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Clear Cut ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Immune Related Genes ◽

Fmdv Replication

Tumor suppressor protein p53 (p53) is a master transcription factor that plays key roles in cell cycle arrest, apoptosis, senescence, and metabolism, as well as regulation of innate immunity during virus infection. In order to facilitate their replication and spreading, viruses have evolved to manipulate p53 function through different strategies, with some requiring active p53 while others demand reduction/inhibition of p53 activity. However, there are no clear-cut reports about the roles of p53 during the infection of foot-and-mouth disease virus (FMDV), the causative agent of a highly contagious foot-and-mouth disease (FMD) of cloven-hoofed animals. Here we showed that p53 level was dynamically regulated during FMDV infection, being degraded at the early infection stage but recovered to the basal level at the late stage. Cells depleted of p53 showed inhibited FMDV replication and enhanced expression of the immune-related genes, whereas overexpression of p53 didn’t affect the viral replication. Viral challenge assay with p53 knockout mice obtained similar results, with viral load decreased, histopathological changes alleviated, and lifespan extended in the p53 knockout mice. Together, these data demonstrate that basal level p53 is required for efficient FMDV replication by suppressing the innate immunity.

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The Kinase STK3 Interacts with the Viral Structural Protein VP1 and Inhibits Foot-and-Mouth Disease Virus Replication

BioMed Research International ◽

10.1155/2017/2481348 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8

Author(s):

Huisheng Liu ◽

Qiao Xue ◽

Qiaoying Zeng ◽

Zixiang Zhu ◽

Haixue Zheng

Keyword(s):

Disease Virus ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Host Cells ◽

Cell Protein ◽

Structural Protein ◽

New Information ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Fmdv Replication

Foot-and-mouth disease virus (FMDV) is the etiological agent of FMD, which affects domestic and wild cloven-hoofed animals. The structural protein VP1 plays an important role in FMDV pathogenesis. However, the interacting partners of VP1 in host cells and the effects of these interactions in FMDV replication remain incompletely elucidated. Here, we identified a porcine cell protein, serine/threonine kinase 3 (STK3), which interacts with FMDV VP1 using the yeast two-hybrid system. The VP1-STK3 interaction was further confirmed by coimmunoprecipitation experiments in human embryonic kidney 293T and porcine kidney 15 (PK-15) cells. The carboxyl-terminal region (amino acids 180–214) of VP1 was essential for its interaction with STK3. The effects of overexpression and underexpressing of STK3 in PK-15 cells were assessed, and the results indicated that STK3 significantly inhibited FMDV replication. Our data expand the role of STK3 during viral infection, provide new information regarding the host cell kinases that are involved in viral replication, and identify potential targets for future antiviral strategies.

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Sec62 Regulates Endoplasmic Reticulum Stress and Autophagy Balance to Affect Foot-and-Mouth Disease Virus Replication

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.707107 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jin’en Wu ◽

Zhihui Zhang ◽

Zhidong Teng ◽

Sahibzada Waheed Abdullah ◽

Shiqi Sun ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Disease Virus ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Jnk Pathway ◽

Fmdv Infection ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Fmdv Replication

Endoplasmic reticulum (ER) stress-induced autophagy is closely associated with viral infection and propagation. However, the intrinsic link between ER stress, autophagy, and viral replication during foot-and-mouth disease virus (FMDV) infection is not fully elucidated. Our previous studies demonstrated that FMDV infection activated the ER stress-associated UPR of the PERK-eIF2a and ATF6 signaling pathway, whereas the IRE1a signaling was suppressed. We found that the activated-ATF6 pathway participated in FMDV-induced autophagy and FMDV replication, while the IRE1α pathway only affected FMDV replication. Further studies indicated that Sec62 was greatly reduced in the later stages of FMDV infection and blocked the activation of the autophagy-related IRE1α-JNK pathway. Moreover, it was also found that Sec62 promoted IRE1a phosphorylation and negatively regulated FMDV proliferation. Importantly, Sec62 may interact with LC3 to regulate ER stress and autophagy balance and eventually contribute to FMDV clearance via fusing with lysosomes. Altogether, these results suggest that Sec62 is a critical molecule in maintaining and recovering ER homeostasis by activating the IRE1α-JNK pathway and delivering autophagosome into the lysosome, thus providing new insights on FMDV-host interactions and novel antiviral therapies.

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Effective inhibition of foot-and-mouth disease virus (FMDV) replication in vitro by vector-delivered microRNAs targeting the 3D gene

Virology Journal ◽

10.1186/1743-422x-8-292 ◽

2011 ◽

Vol 8 (1) ◽

pp. 292 ◽

Cited By ~ 14

Author(s):

Junzheng Du ◽

Shandian Gao ◽

Jihuai Luo ◽

Guofeng Zhang ◽

Guozheng Cong ◽

...

Keyword(s):

Disease Virus ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Mouth Disease Virus ◽

Effective Inhibition ◽

Foot And Mouth ◽

Fmdv Replication ◽

3D Gene

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Cellular Vimentin Interacts with Foot-and-Mouth Disease Virus Nonstructural Protein 3A and Negatively Modulates Viral Replication

Journal of Virology ◽

10.1128/jvi.00273-20 ◽

2020 ◽

Vol 94 (16) ◽

Cited By ~ 2

Author(s):

Xueqing Ma ◽

Ying Ling ◽

Pinghua Li ◽

Pu Sun ◽

Yimei Cao ◽

...

Keyword(s):

Disease Virus ◽

Virus Replication ◽

Nonstructural Protein ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Amino Acid Residues ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Fmdv Replication

ABSTRACT Nonstructural protein 3A of foot-and-mouth disease virus (FMDV) is a partially conserved protein of 153 amino acids that is in most FMDVs examined to date, and it plays important roles in virus replication, virulence, and host range. To better understand the role of 3A during FMDV infection, we used coimmunoprecipitation followed by mass spectrometry to identify host proteins that interact with 3A in FMDV-infected cells. Here, we report that cellular vimentin is a host binding partner for 3A. The 3A-vimentin interaction was further confirmed by coimmunoprecipitation, glutathione S-transferase (GST) pull down, and immunofluorescence assays. Alanine-scanning mutagenesis indicated that amino acid residues 15 to 21 at the N-terminal region of the FMDV 3A are responsible for the interaction between 3A and vimentin. Using reverse genetics, we demonstrate that mutations in 3A that disrupt the interaction between 3A and vimentin are also critical for virus growth. Overexpression of vimentin significantly suppressed the replication of FMDV, whereas knockdown of vimentin significantly enhanced FMDV replication. However, chemical disruption of the vimentin network by acrylamide resulted in a significant decrease in viral yield, suggesting that an intact vimentin network is needed for FMDV replication. These results indicate that vimentin interacts with FMDV 3A and negatively regulates FMDV replication and that the vimentin-3A interaction is essential for FMDV replication. This study provides information that should be helpful for understanding the molecular mechanism of FMDV replication. IMPORTANCE Foot-and-mouth disease virus (FMDV) nonstructural protein 3A plays important roles in virus replication, host range, and virulence. To further understand the role of 3A during FMDV infection, identification of host cell factors that interact with FMDV 3A is needed. Here, we found that vimentin is a direct binding partner of FMDV 3A, and manipulation of vimentin has a negative effect on virus replication. We also demonstrated that amino acid residues 15 to 21 at the N-terminal region of the FMDV 3A are responsible for the interaction between 3A and vimentin and that the 3A-vimentin interaction is critical for viral replication since the full-length cDNA clone harboring mutations in 3A, which were disrupt 3A-vimentin reactivity, could not produce viable virus progeny. This study provides information that not only provides us a better understanding of the mechanism of FMDV replication but also helps in the development of novel antiviral strategies in the future.

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The Leader Proteinase of Foot-and-Mouth Disease Virus Inhibits the Induction of Beta Interferon mRNA and Blocks the Host Innate Immune Response

Journal of Virology ◽

10.1128/jvi.80.4.1906-1914.2006 ◽

2006 ◽

Vol 80 (4) ◽

pp. 1906-1914 ◽

Cited By ~ 146

Author(s):

Teresa de los Santos ◽

Sonia de Avila Botton ◽

Rudi Weiblen ◽

Marvin J. Grubman

Keyword(s):

Disease Virus ◽

Foot And Mouth Disease ◽

Mrna Translation ◽

Mouth Disease ◽

Wild Type Virus ◽

Β Protein ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Fmdv Replication

ABSTRACT We have previously shown that the leader proteinase (Lpro) of foot-and-mouth disease virus (FMDV) blocks cap-dependent mRNA translation and that a genetically engineered FMDV lacking the leader proteinase coding region (A12-LLV2) is attenuated in cell culture and susceptible animals. The attenuated phenotype apparently is a consequence of the inability of A12-LLV2 to block the expression of type I interferon (IFN-α/β) protein, resulting in IFN-induced inhibition of FMDV replication. Here we show that in addition to preventing IFN-α/β protein synthesis, Lpro reduces the level of immediate-early induction of IFN-β mRNA and IFN-stimulated gene products such as double-stranded RNA-dependent protein kinase R (PKR), 2′,5′-oligoadenylate synthetase, and Mx1 mRNAs in swine cells. Down-regulation of cellular PKR by RNA interference did not affect wild-type virus yield but resulted in a higher yield of A12-LLV2, indicating a direct role of PKR in controlling FMDV replication in the natural host. The observation that Lpro controls the transcription of genes involved in innate immunity reveals a novel role of this protein in antagonizing the cellular response to viral infection.

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High resolution surface structure of foot-and-mouth disease virus

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100082741 ◽

1978 ◽

Vol 36 (2) ◽

pp. 376-377

Author(s):

S. S. Breese ◽

H. L. Bachrach

Keyword(s):

Electron Microscopy ◽

High Resolution ◽

Surface Structure ◽

Disease Virus ◽

Potassium Phosphate ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Physical Measurements ◽

Mouth Disease Virus ◽

Foot And Mouth

Models for the structure of foot-and-mouth disease virus (FMDV) have been proposed from chemical and physical measurements (Brown, et al., 1970; Talbot and Brown, 1972; Strohmaier and Adam, 1976) and from rotational image-enhancement electron microscopy (Breese, et al., 1965). In this report we examine the surface structure of FMDV particles by high resolution electron microscopy and compare it with that of particles in which the outermost capsid protein VP3 (ca. 30, 000 daltons) has been split into smaller segments, two of which VP3a and VP3b have molecular weights of about 15, 000 daltons (Bachrach, et al., 1975).Highly purified and concentrated type A12, strain 119 FMDV (5 mg/ml) was prepared as previously described (Bachrach, et al., 1964) and stored at 4°C in 0. 2 M KC1-0. 5 M potassium phosphate buffer at pH 7. 5. For electron microscopy, 1. 0 ml samples of purified virus and trypsin-treated virus were dialyzed at 4°C against 0. 2 M NH4OAC at pH 7. 3, deposited onto carbonized formvar-coated copper screens and stained with phosphotungstic acid, pH 7. 3.

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