scholarly journals Foot-and-Mouth Disease Virus Evades Innate Immune Response by 3C-Targeting of MDA5

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 271
Author(s):  
Hyejin Kim ◽  
Ah-Young Kim ◽  
Jieun Choi ◽  
Sun Young Park ◽  
Sang Hyun Park ◽  
...  
Keyword(s):  
Immune Response ◽  
Protein Expression ◽  
Innate Immune Response ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Innate Immune ◽  
Type I ◽  
Fmdv Infection ◽  
Mouth Disease Virus ◽  
Foot And Mouth

Foot-and-mouth disease (FMD) is a highly contagious disease caused by FMD virus (FMDV) in cloven-hoofed animals. Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are representative receptors in the cytoplasm for the detection of viral RNA and trigger antiviral responses, leading to the production of type I interferon. Although MDA5 is a crucial receptor for sensing picornavirus RNA, the interplay between MDA5 and FMDV is relatively unknown compared to the interplay between RIG-I and FMDV. Here, we observed that the FMDV infection inhibits MDA5 protein expression. Of the non-structural proteins, the Lb and 3C proteinases (Lbpro and 3Cpro) were identified to be primarily responsible for this inhibition. However, the inhibition by 3Cpro was independent of proteasome, lysosome and caspase-dependent pathway and was by 3C protease activity. A direct interaction between 3Cpro and MDA5 protein was observed. In conclusion, this is the first report that 3Cpro inhibits MDA5 protein expression as a mechanism to evade the innate immune response during FMDV infection. These results elucidate the pathogenesis of FMDV and provide fundamental insights for the development of a novel vaccine or therapeutic agent.

scholarly journals Synthetic RNAs Mimicking Structural Domains in the Foot-and-Mouth Disease Virus Genome Elicit a Broad Innate Immune Response in Porcine Cells Triggered by RIG-I and TLR Activation

Viruses ◽  
2015 ◽  
Vol 7 (7) ◽  
pp. 3954-3973 ◽  
Author(s):  
Belén Borrego ◽  
Miguel Rodríguez-Pulido ◽  
Concepción Revilla ◽  
Belén Álvarez ◽  
Francisco Sobrino ◽  
...  
Keyword(s):  
Immune Response ◽  
Disease Virus ◽  
Innate Immune Response ◽  
Foot And Mouth Disease ◽  
Virus Genome ◽  
Mouth Disease ◽  
Innate Immune ◽  
Structural Domains ◽  
Mouth Disease Virus ◽  
Foot And Mouth

scholarly journals Foot-and-mouth disease virus 5’-terminal S fragment is required for replication and modulation of the innate immune response in host cells

Virology ◽  
2017 ◽  
Vol 512 ◽  
pp. 132-143 ◽  
Author(s):  
Anna Kloc ◽  
Fayna Diaz-San Segundo ◽  
Elizabeth A. Schafer ◽  
Devendra K. Rai ◽  
Mary Kenney ◽  
...  
Keyword(s):  
Immune Response ◽  
Disease Virus ◽  
Innate Immune Response ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Innate Immune ◽  
Host Cells ◽  
Mouth Disease Virus ◽  
Foot And Mouth

scholarly journals Interferon-Induced Protection against Foot-and-Mouth Disease Virus Infection Correlates with Enhanced Tissue-Specific Innate Immune Cell Infiltration and Interferon-Stimulated Gene Expression

2009 ◽  
Vol 84 (4) ◽  
pp. 2063-2077 ◽  
Author(s):  
Fayna Diaz-San Segundo ◽  
Mauro P. Moraes ◽  
Teresa de los Santos ◽  
Camila C. A. Dias ◽  
Marvin J. Grubman
Keyword(s):  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Innate Immune ◽  
Lymphoid Tissues ◽  
Type I ◽  
Oligoadenylate Synthetase ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Ifn Γ

ABSTRACT Previously, we demonstrated that type I interferon (IFN-α/β) or a combination of IFN-α/β and type II IFN (IFN-γ) delivered by a replication-defective human adenovirus 5 (Ad5) vector protected swine when challenged 1 day later with foot-and-mouth disease virus (FMDV). To gain a more comprehensive understanding of the mechanism of protection induced by IFNs, we inoculated groups of six swine with Ad5-vectors containing these genes, challenged 1 day later and euthanized 2 animals from each group prior to (1 day postinoculation [dpi]) and at 1 (2 dpi) and 6 days postchallenge (7 dpi). Blood, skin, and lymphoid tissues were examined for IFN-stimulated gene (ISG) induction and infiltration by innate immune cells. All IFN-inoculated animals had delayed and decreased clinical signs and viremia compared to the controls, and one animal in the IFN-α treated group did not develop disease. At 1 and 2 dpi the groups inoculated with the IFNs had increased numbers of dendritic cells and natural killer cells in the skin and lymph nodes, respectively, as well as increased levels of several ISGs compared to the controls. In particular, all tissues examined from IFN-treated groups had significant upregulation of the chemokine 10-kDa IFN-γ-inducible protein 10, and preferential upregulation of 2′,5′-oligoadenylate synthetase, Mx1, and indoleamine 2,3-dioxygenase. There was also upregulation of monocyte chemotactic protein 1 and macrophage inflammatory protein 3α in the skin. These data suggest that there is a complex interplay between IFN-induced immunomodulatory and antiviral activities in protection of swine against FMDV.

scholarly journals Effect of Foot-and-Mouth Disease Vaccination on Acute Phase Immune Response and Anovulation in Hanwoo (Bos taurus coreanae)

Vaccines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 419
Author(s):  
Daehyun Kim ◽  
Joonho Moon ◽  
Jaejung Ha ◽  
Doyoon Kim ◽  
Junkoo Yi
Keyword(s):  
Immune Response ◽  
Artificial Insemination ◽  
Bos Taurus ◽  
Foot And Mouth Disease ◽  
Test Group ◽  
Mouth Disease ◽  
Control Group ◽  
Amyloid A ◽  
Mouth Disease Virus ◽  
Foot And Mouth

Vaccination against foot-and-mouth disease is the most common method for preventing the spread of the disease; the negative effects include miscarriage, early embryo death, lower milk production, and decreased growth of fattening cattle. Therefore, in this study, we analyze the side effects of vaccination by determining the acute immune response and ovulation rate after vaccinating cows for foot-and-mouth disease. The test axis was synchronized with ovulation using 100 Hanwoo (Bos taurus coreanae) cows from the Gyeongsangbuk-do Livestock Research Institute; only individuals with estrus confirmed by ovarian ultrasound were used for the test. All test axes were artificially inseminated 21 days after the previous estrus date. The control group was administered 0.9% normal saline, the negative control was injected intramuscularly with lipopolysaccharide (LPS; 0.5 µg/kg), and the test group was administered a foot-and-mouth disease virus vaccine (FMDV vaccine; bioaftogen, O and A serotypes, inactivated vaccine) 2, 9, and 16 days before artificial insemination. White blood cells and neutrophils increased significantly 1 day after vaccination, and body temperature in the rumen increased for 16 h after vaccination. Ovulation was detected 1 day after artificial fertilization by ovarian ultrasound. The ovulation rates were as follows: control 89%, LPS 60%, FMDV vaccine (−2 d) 50%, FMDV vaccine (−9 d) 75%, and FMDV vaccine (−16 d) 75%. In particular, the FMDV vaccine (−2 d) test group confirmed that ovulation was delayed for 4 days after artificial insemination. In addition, it was confirmed that it took 9 days after inoculation for the plasma contents of haptoglobin and serum amyloid A to recover to the normal range as the main acute immune response factors. The conception rate of the FMDV vaccine (−2 d) group was 20%, which was significantly lower than that of the other test groups.

scholarly journals Proteomics Analysis of Porcine Serum Proteins by LC-MS/MS after Foot-and-Mouth Disease Virus (FMDV) Infection

2011 ◽  
Vol 73 (12) ◽  
pp. 1569-1572 ◽  
Author(s):  
Yongjie LIU ◽  
Keshan ZHANG ◽  
Haixue ZHENG ◽  
Youjun SHANG ◽  
Jianhong GUO ◽  
...  
Keyword(s):  
Disease Virus ◽  
Serum Proteins ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Proteomics Analysis ◽  
Porcine Serum ◽  
Fmdv Infection ◽  
Mouth Disease Virus ◽  
Foot And Mouth

scholarly journals The Foot-and-Mouth Disease Carrier State Divergence in Cattle

2016 ◽  
Vol 90 (14) ◽  
pp. 6344-6364 ◽  
Author(s):  
Carolina Stenfeldt ◽  
Michael Eschbaumer ◽  
Steven I. Rekant ◽  
Juan M. Pacheco ◽  
George R. Smoliga ◽  
...  
Keyword(s):  
Foot And Mouth Disease ◽  
Antiviral Response ◽  
Carrier State ◽  
Gamma Interferon ◽  
Mouth Disease ◽  
Fmdv Infection ◽  
Mouth Disease Virus ◽  
Follicle Associated Epithelium ◽  
Foot And Mouth ◽  
Host Antiviral Response

ABSTRACTThe pathogenesis of persistent foot-and-mouth disease virus (FMDV) infection was investigated in 46 cattle that were either naive or had been vaccinated using a recombinant, adenovirus-vectored vaccine 2 weeks before challenge. The prevalence of FMDV persistence was similar in both groups (62% in vaccinated cattle, 67% in nonvaccinated cattle), despite vaccinated cattle having been protected from clinical disease. Analysis of antemortem infection dynamics demonstrated that the subclinical divergence between FMDV carriers and animals that cleared the infection had occurred by 10 days postinfection (dpi) in vaccinated cattle and by 21 dpi in nonvaccinated animals. The anatomic distribution of virus in subclinically infected, vaccinated cattle was restricted to the pharynx throughout both the early and the persistent phases of infection. In nonvaccinated cattle, systemically disseminated virus was cleared from peripheral sites by 10 dpi, while virus selectively persisted within the nasopharynx of a subset of animals. The quantities of viral RNA shed in oropharyngeal fluid during FMDV persistence were similar in vaccinated and nonvaccinated cattle. FMDV structural and nonstructural proteins were localized to follicle-associated epithelium of the dorsal soft palate and dorsal nasopharynx in persistently infected cattle. Host transcriptome analysis of tissue samples processed by laser capture microdissection indicated suppression of antiviral host factors (interferon regulatory factor 7, CXCL10 [gamma interferon-inducible protein 10], gamma interferon, and lambda interferon) in association with persistent FMDV. In contrast, during the transitional phase of infection, the level of expression of IFN-λ mRNA was higher in follicle-associated epithelium of animals that had cleared the infection. This work provides novel insights into the intricate mechanisms of FMDV persistence and contributes to further understanding of this critical aspect of FMDV pathogenesis.IMPORTANCEThe existence of a prolonged, asymptomatic carrier state is a political impediment for control and potential eradication of foot-and-mouth disease (FMD). When FMD outbreaks occur, they are often extinguished by massive depopulation of livestock due to the fear that some animals may have undiagnosed subclinical infection, despite uncertainty over the biological relevance of FMD virus (FMDV) persistence. The work described here elucidates aspects of the FMDV carrier state in cattle which may facilitate identification and/or abrogation of asymptomatic FMDV infection. The divergence between animals that clear infection and those that develop persistent infection was demonstrated to occur earlier than previously established. The host antiviral response in tissues maintaining persistent FMDV was downregulated, whereas upregulation of IFN-λ mRNA was found in the epithelium of cattle that had recently cleared the infection. This suggests that the clearing of FMDV infection is associated with an enhanced mucosal antiviral response, whereas FMDV persistence is associated with suppression of the host antiviral response.

Establishment of persistent foot-and-mouth disease virus (FMDV) infection in MDBK cells

2015 ◽  
Vol 160 (10) ◽  
pp. 2503-2516 ◽  
Author(s):  
Lela Kopliku ◽  
Anthony Relmy ◽  
Aurore Romey ◽  
Kamila Gorna ◽  
Stephan Zientara ◽  
...  
Keyword(s):  
Disease Virus ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Fmdv Infection ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Mdbk Cells

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 Innate Immune Defenses Induced by CpG Do Not Promote Vaccine-Induced Protection against Foot-and-Mouth Disease Virus in Pigs

2009 ◽  
Vol 16 (8) ◽  
pp. 1151-1157 ◽  
Author(s):  
M. P. Alves ◽  
L. Guzylack-Piriou ◽  
V. Juillard ◽  
J.-C. Audonnet ◽  
T. Doel ◽  
...  
Keyword(s):  
Disease Virus ◽  
Large Scale ◽  
Control Strategies ◽  
Foot And Mouth Disease ◽  
Mouth Disease ◽  
Innate Immune ◽  
Noticeable Effect ◽  
Mouth Disease Virus ◽  
Foot And Mouth ◽  
Natural Hosts

ABSTRACT Emergency vaccination as part of the control strategies against foot-and-mouth disease virus (FMDV) has the potential to limit virus spread and reduce large-scale culling. To reduce the time between vaccination and the onset of immunity, immunostimulatory CpG was tested for its capacity to promote early protection against FMDV challenge in pigs. To this end, CpG 2142, an efficient inducer of alpha interferon, was injected intramuscularly. Increased transcription of Mx1, OAS, and IRF-7 was identified as a sensitive measurement of CpG-induced innate immunity, with increased levels detectable to at least 4 days after injection of CpG formulated with Emulsigen. Despite this, CpG combined with an FMD vaccine did not promote protection. Pigs vaccinated 2 days before challenge had disease development, which was at least as acute as that of unvaccinated controls. All pigs vaccinated 7 days before challenge were protected without a noticeable effect of CpG. In summary, our results demonstrate the caution required when translating findings from mouse models to natural hosts of FMDV.

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