Robust Protection against Highly Virulent Foot-and-Mouth Disease Virus in Swine by Combination Treatment with Recombinant Adenoviruses Expressing Porcine Alpha and Gamma Interferons and Multiple Small Interfering RNAs

Kim, Su-Mi; Park, Jong Hyeon; Lee, Kwang‐Nyeong; Kim, Se-Kyung; You, Su-Hwa; Kim, Taeseong; Tark, Dongseob; Lee, Hyang-Sim; Seo, Min-Goo; Kim, Byounghan

doi:10.1128/jvi.00766-15

Cited by 27 publications

(18 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Examples include the use of Ad5 vectors expressing alpha interferon (IFN-␣) (11), IFN-␤ (12), IFN-␥ (13), IFN- (14), and IFN-␣/␥ and FMDV-specific small interfering RNA (siRNAs) (15) to protect swine. In addition, combinational approaches such as Ad5-IFN-␣ and an Ad5 subunit vaccine delivering FMD empty capsids have successfully shortened the window in which vaccinated animals can still become infected (16).…”

Section: Importancementioning

confidence: 99%

Constitutively Active IRF7/IRF3 Fusion Protein Completely Protects Swine against Foot-and-Mouth Disease

Ramírez-Carvajal¹,

Segundo

Ramírez-Medina³

et al. 2016

J Virol

View full text Add to dashboard Cite

Foot-and-mouth disease (FMD) remains one of the most devastating livestock diseases around the world. Several serotype-specific vaccine formulations exist, but they require about 5 to 7 days to induce protective immunity. Our previous studies have shown that a constitutively active fusion protein of porcine interferon (IFN) regulatory factors (IRF) 7 and 3 [IRF7/3(5D)] strongly induced type I IFN and antiviral genes in vitro and prevented mortality in an FMD mouse model when delivered with a replication-defective adenoviral vector [Ad5-poIRF7/3(5D)]. Here, we demonstrate that pigs treated with 10 8 , 10 9 , or 10 10 PFU of Ad5-poIRF7/3(5D) 24 h before FMDV challenge were fully protected from FMD clinical signs and did not develop viremia, virus shedding or antibodies against FMDV nonstructural proteins. Pigs treated with Ad5-poIRF7/3(5D) had higher levels of IFN and antiviral activity in serum, and upregulated expression of several IFN-stimulated genes in peripheral blood mononuclear cells, compared to pigs treated with Ad5-Blue vector control. Importantly, treatment of porcine cultured cells with Ad5-poIRF7/3(5D) inhibited the replication of all 7 FMDV serotypes. In vitro experiments using cultured embryonic fibroblasts derived from IFN receptor knockout mice suggested that the antiviral response induced by Ad5-poIRF7/3(5D) was dependent on type I and III IFN pathways; however, experiments with mice demonstrated that a functional type I IFN pathway mediates Ad5-poIRF7/3(5D) protection conferred in vivo. Our studies demonstrate that inoculation with Ad5-poIRF7/3(5D) completely protects swine against FMD by inducing a strong type I IFN response and highlights its potential application to rapidly and effectively prevent FMDV replication and dissemination. IMPORTANCEFoot-and-mouth disease virus (FMDV) causes a fast-spreading disease that affects farm animals, with economically and socially devastating consequences. Our study shows that inoculation with a constitutively active transcription factor, namely, a fusion protein of porcine interferon (IFN) regulatory factors (IRF) 7 and 3 delivered by an adenovirus vector [Ad5-poIRF7/3(5D)], is a new effective treatment to prevent FMD in swine. Animals pretreated with Ad5-poIRF7/3(5D) 1 day before being exposed to FMDV were completely protected from viral replication and clinical disease. It is noteworthy that the doses of Ad5-poIRF7/ 3(5D) required for protection are lower than those previously reported for similar approaches using Ad5 vectors delivering type I, II, or III IFN, suggesting that this novel strategy would be economically appealing to counteract FMD. Our results also indicate that a dynamic interplay among different components of pigs' innate immune defenses allows potent antiviral effects after Ad5-poIF7/3(5D) administration. F oot-and-mouth disease virus (FMDV) causes an economically, socially devastating, fast-spreading disease that affects a wide range of farm and wild cloven-hooved animals (1). The existence of seven serotypes (A, Asia1, C, O, a...

show abstract

Section: Importancementioning

confidence: 99%

Constitutively Active IRF7/IRF3 Fusion Protein Completely Protects Swine against Foot-and-Mouth Disease

Ramírez-Carvajal¹,

Segundo

Ramírez-Medina³

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…In future studies, we plan to assess the antiviral effect of these siRNAs with wild-type RVFV isolates and in various experimental animal models including murine, ruminant, and non-human primates. Furthermore, we might examine co-administration of siRNAs in conjunction with subunit vaccines; this approach could provide protection during the period of the immunity gap before the vaccine provides efficient protection (Kim et al, 2015). Adopting such a vaccination scheme could enhance vaccine efficacy and improve the overall efficiency of RVF vaccination programs.…”

Section: Resultsmentioning

confidence: 99%

Short Interfering RNA Inhibits Rift Valley Fever Virus Replication and Degradation of Protein Kinase R in Human Cells

Faburay

Richt

2016

Front. Microbiol.

View full text Add to dashboard Cite

Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing severe outbreaks in humans and livestock in sub-Saharan Africa and the Arabian Peninsula. Human infections are characterized by fever, sometimes leading to encephalitis, retinitis, hemorrhagic fever, and occasionally death. There are currently no fully licensed vaccines or effective therapies for human use. Gene silencing mediated by double-stranded short interfering RNA (siRNA) is a sequence-specific, highly conserved mechanism in eukaryotes, which serves as an antiviral defense mechanism. Here, we demonstrate that siRNA duplexes directed against the RVFV nucleoprotein can effectively inhibit RVFV replication in human (MRC5 cells) and African green monkey cells (Vero E6 cells). Using these cells, we demonstrate that individual or complex siRNAs, targeting the RVFV nucleoprotein gene completely abrogate viral protein expression and prevent degradation of the host innate antiviral factor, protein kinase R (PKR). Importantly, pre-treatment of cells with the nucleoprotein-specific siRNAs markedly reduces the virus titer. The antiviral effect of the siRNAs was not attributable to interferon or the interferon response effector molecule, PKR. Thus, the antiviral activity of RVFV nucleoprotein-specific siRNAs may provide novel therapeutic strategy against RVFV infections in animals and humans.

show abstract

“…Expression of small hairpin RNAs specific for the FMDV 3D polymerase and the structural 1D protein could partially protect pigs against challenge [78]. RDAd delivering small interfering RNA, IFN-α, and IFN-γ enhanced anti-FMDV effects and was effective against multiple FMDV serotypes [79]. RNA interference delivered by RDAd could, therefore, be used as a fast-acting antiviral.…”

Section: Rna Interference Of Viral Replication and Enhanced Antigen Pmentioning

confidence: 99%

Adenovirus as Tools in Animal Health

Rojas¹,

Sevilla²,

Martı́n³

2019

Adenoviruses

View full text Add to dashboard Cite

Adenoviruses have long been identified as good candidates for use as viral vectors in gene therapy and as vaccines. These viruses can infect multiple cell types, while in division or in quiescence, and are relatively easy to manipulate so that parts of their genome can be replaced with exogenous genes. Progressive safety improvements in replication-deficient adenoviral vectors have been achieved with the second and third generation, and ending with the gutless adenoviral vectors. Adenoviral vectors are immunogenic and can act as adjuvants. Nonetheless, the potency of human recombinant adenoviral vaccines was below expectations in clinical trials mainly because of the pre-existing adenoviral immunity found in the general population. This drawback can however become advantageous in animal health, as no previous immunity to human adenoviral vectors exists in animals. Other viral vectors viruses are used as vaccine, but adenoviruses remain the most employed and promising recombinant vector in veterinary medicine. In this chapter, we review the generation of adenoviral vectors, the immune response they trigger, and their advantages and disadvantages for veterinary use in terms of safety and efficacy. This chapter also describes how recombinant adenoviral vectors can be integrated as tools for vaccination and immunomodulation in veterinary medicine.

show abstract

Robust Protection against Highly Virulent Foot-and-Mouth Disease Virus in Swine by Combination Treatment with Recombinant Adenoviruses Expressing Porcine Alpha and Gamma Interferons and Multiple Small Interfering RNAs

Cited by 27 publications

References 41 publications

Constitutively Active IRF7/IRF3 Fusion Protein Completely Protects Swine against Foot-and-Mouth Disease

Constitutively Active IRF7/IRF3 Fusion Protein Completely Protects Swine against Foot-and-Mouth Disease

Short Interfering RNA Inhibits Rift Valley Fever Virus Replication and Degradation of Protein Kinase R in Human Cells

Adenovirus as Tools in Animal Health

Contact Info

Product

Resources

About