Collaboration work between FADD, NVRQS and Pirbright Lab, UK ( 07/09/27 ) | |||||
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Part | Charger | leeyh | date | 07/09/27 | |
Title : Infection-interference strategy for mucosal-defense against FMD
Period : 2003.7-2006.6(3 years)
Summary (Part I):
Foot-and-mouth disease (FMD) is highly contagious disease that affects cloven-hoofed animals, such as cattle, swine and sheep. Current vaccines induce protective response at from 7 to 15 days post vaccination. However, the FMD can rapidly transmit and has short incubation period, and the clinical signs could appear 2 days post exposure. Routine vaccination might not be effective for early protection in the situation of the explosive outbreak. So in this study we developed diverse kinds of anti-viral constructs using adenovectors for inducing innate or adaptive immunity.
Firstly, type I alpha/beta interferon (IFN-α/β) is the first line of host cell defense against virus infection. To induce a early protective response against foot and mouth disease, the recombinant human adenoviruses (Ad-HIFN-α, Ad-PIFN-β/PIL-18) expressing human interferon-α (HIFN-α), fusion protein of porcine interferon-β (PIFN-β) and porcine interleukin-18 (IL-18) were constructed. For analysis of anti-FMDV effect, mice were applied with Ad-HIFN-α, Ad-PIFN-β/PIL-18, and cocktail of Ad-HIFN-α and Ad-PIFN-β/PIL-18. The survival data in suckling ICR mice were recorded after challenge following administration of various adenoviruses by the intra-peritoneal (IP) route. Inhibition of FMDV replication was evaluated by indirect antigen ELISA. They showed inhibition of FMDV replication after administration of Ad-HIFN-α, Ad-PIFN-β/ PIL-18 in IBRS-2 (porcine kidney) cells. The administration of Ad-HIFN-α showed the best inhibition in FMDV replication. These adenoviral recombinants could inhibit FMDV replication in mice, and are supposed to be a control method for the early protection for FMD infection.
Secondly, RNA interference (RNAi) is a rapid anti-viral therapeutic approach and could be applied with routine vaccination. In this study, we demonstrate adenovirus-mediated short hairpin RNAs (shRNAs) targeting nonstructural protein (NSP) genes are effective to inhibit FMDV replication in vitro and in vivo. Human adenoviruses expressing shRNAs targeting 3C/2B/3D region effectively suppress FMDV (O/SKR/2002) replication in swine IBRS-2 cells and suckling mice. We enhanced the antiviral effect by mixture of two adenovirus constructs and showed potential of long-lasting antiviral effect by additional injection in vivo. There are seven serotypes: A, O, C, Asia1, SAT 1, SAT 2, and SAT 3 in FMDV, but the numerous subtypes have evolved within each serotype. Adenovirus-mediated targeting NSP genes of FMDV could cross inhibit variant FMDV serotypes and applied to broad host range
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