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Constitutively Active IRF7/IRF3 Fusion Protein Completely Protects Swine against
Foot-and-Mouth Disease
#MMPMID27466421
Ramírez-Carvajal L
; Diaz-San Segundo F
; Ramirez-Medina E
; Rodríguez LL
; de Los Santos T
J Virol
2016[Oct]; 90
(19
): 8809-21
PMID27466421
show ga
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. IMPORTANCE:
Foot-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.
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