The Kinase STK3 Interacts with the Viral Structural Protein VP1 and Inhibits Foot-and-Mouth Disease Virus 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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Foot-and-mouth disease virus non-structural protein 3A modulates cellular innate immune responses to influence host tropism

Access Microbiology ◽

10.1099/acmi.ac2020.po0377 ◽

2020 ◽

Vol 2 (7A) ◽

Author(s):

Soumendu Chakravarti ◽

Caroline Wright ◽

Emma Howes ◽

Richard Kock ◽

Terry Jackson ◽

...

Keyword(s):

Disease Virus ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Economic Losses ◽

Structural Protein ◽

Host Tropism ◽

C Terminus ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Species Specific

The picornavirus foot-and-mouth disease virus (FMDV) is responsible for one of the most significant diseases of livestock, leading to large economic losses due to reduced productivity and trade embargoes for areas not certified as disease-free. The picornavirus non-structural protein 3A is involved in replication of the viral RNA genome and is implicated in host tropism of several picornaviruses. Deletions in the C-terminus of 3A have been observed in FMDV outbreaks specific for swine and such viruses are non-pathogenic in cattle. The mechanism for species specific attenuation of FMDV is unknown. We have shown that FMDV containing a C-terminal deletion in 3A is attenuated in bovine cell culture and that the attenuated phenotype can be reversed by the JAK1/2 inhibitor Ruxolitinib (Rux), identifying a role for the induction of interferon stimulated genes (ISGs) in the restricted bovine tropism of the 3A-deleted virus.

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Ability of Foot-and-Mouth Disease Virus To Form Plaques in Cell Culture Is Associated with Suppression of Alpha/Beta Interferon

Journal of Virology ◽

10.1128/jvi.73.12.9891-9898.1999 ◽

1999 ◽

Vol 73 (12) ◽

pp. 9891-9898 ◽

Cited By ~ 120

Author(s):

Jarasvech Chinsangaram ◽

Maria E. Piccone ◽

Marvin J. Grubman

Keyword(s):

Antiviral Activity ◽

Disease Virus ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Host Cells ◽

Wild Type Virus ◽

Beta Interferon ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Alpha Beta

ABSTRACT A genetic variant of foot-and-mouth disease virus lacking the leader proteinase coding region (A12-LLV2) is attenuated in both cattle and swine and, in contrast to wild-type virus (A12-IC), does not spread from the initial site of infection after aerosol exposure of bovines. We have identified secondary cells from susceptible animals, i.e., bovine, ovine, and porcine animals, in which infection with A12-LLV2, in contrast to A12-IC infection, does not produce plaques; this result indicates that this virus cannot spread from the site of initial infection to neighboring cells. Nevertheless, A12-LLV2 can infect these cells, but cytopathic effects and virus yields are significantly reduced compared to those seen with A12-IC infection. Reverse transcription-PCR analysis demonstrates that both A12-LLV2 and A12-IC induce the production of alpha/beta interferon (IFN-α/β) mRNA in host cells. However, only supernatants from A12-LLV2-infected cells have significant antiviral activity. The antiviral activity in supernatants from A12-LLV2-infected embryonic bovine kidney cells is IFN-α/β specific, as assayed with mouse embryonic fibroblast cells with or without IFN-α/β receptors. The results obtained with cell cultures demonstrate that the ability of A12-IC to form plaques is associated with the suppression of IFN-α/β expression and suggest a role for this host factor in the inability of A12-LLV2 to spread and cause disease in susceptible animals.

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Diagnostic application of recombinant non-structural protein 3A to detect antibodies induced by foot-and-mouth disease virus infection

Biologicals ◽

10.1016/j.biologicals.2016.02.004 ◽

2016 ◽

Vol 44 (3) ◽

pp. 157-162 ◽

Cited By ~ 8

Author(s):

Jitendra K. Biswal ◽

Rajeev Ranjan ◽

Bramhadev Pattnaik

Keyword(s):

Virus Infection ◽

Disease Virus ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Structural Protein ◽

Diagnostic Application ◽

Mouth Disease Virus ◽

Foot And Mouth

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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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Relevance of the N-terminal and major hydrophobic domains of non-structural protein 3A in the replicative process of a DNA-launched foot-and-mouth disease virus replicon

Archives of Virology ◽

10.1007/s00705-018-3795-9 ◽

2018 ◽

Vol 163 (7) ◽

pp. 1769-1778 ◽

Cited By ~ 1

Author(s):

Cecilia M. Lotufo ◽

Maximiliano Wilda ◽

Adrian N. Giraldez ◽

Pablo R. Grigera ◽

Nora M. Mattion

Keyword(s):

Disease Virus ◽

Foot And Mouth Disease ◽

Mouth Disease ◽

Structural Protein ◽

Mouth Disease Virus ◽

Foot And Mouth

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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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Early origin and global colonisation of foot-and-mouth disease virus

Scientific Reports ◽

10.1038/s41598-020-72246-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Pakorn Aiewsakun ◽

Nakarin Pamornchainavakul ◽

Chaidate Inchaisri

Keyword(s):

Disease Virus ◽

Foot And Mouth Disease ◽

Epidemiological Data ◽

Mouth Disease ◽

Recent Common Ancestor ◽

Structural Protein ◽

Most Recent Common Ancestor ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Early Origin

Abstract In this study, we compiled 84-year worth (1934–2017) of genomic and epidemiological data of foot-and-mouth disease virus (FMDV), and performed comprehensive analyses to determine its early origin and transmission route. We found that recombination is a key feature of FMDV, and that the genomic regions coding for structural and non-structural proteins have markedly different evolutionary histories, and evolve at different rates. Despite all of these differences, analyses of both structural and non-structural protein coding regions consistently suggested that the most recent common ancestor of FMDV could be dated back to the Middle Age, ~ 200 to 300 years earlier than previously thought. The ancestors of the Euro-Asiatic and SAT strains could be dated back to the mid-seventeenth century, and to the mid-fifteenth to mid-sixteenth century, respectively. Our results implicated Mediterranean counties as an early geographical origin of FMDV before spreading to Europe and subsequently to Asia and South America.

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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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