Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically relevant viral pathogens in pigs and causes substantial losses in the pig industry worldwide each year. At present, PRRSV vaccines do not effectively prevent and control this disease. Consequently, it is necessary to develop new antiviral strategies to compensate for the inefficacy of the available vaccines. Histone deacetylase 6 (HDAC6) is an important member of the histone deacetylase family that is responsible for regulating many important biological processes. Studies have shown that HDAC6 has anti-viral activities during the viral life cycle. However, whether HDAC6 overexpression enhances resistance to PRRSV in pigs remains unknown. In this study, we used a somatic cell cloning method to produce transgenic (TG) pigs that constitutively overexpress porcine HDAC6. These TG pigs showed germ line transmission with continued overexpression of HDAC6. In vitro, virus-challenged porcine alveolar macrophages (PAMs) overexpressed HDAC6, which suppressed viral gene expression and PRRSV production. In vivo, resistance to PRRSV in TG pigs was evaluated by direct or cohabitation mediated infection with a highly pathogenic PRRSV (HP-PRRSV) strain. Compared with non-TG (NTG) siblings, TG pigs showed a significantly lower viral load in the lungs and an extended survival time after infection with HP-PRRSV via intramuscular injection. In the cohabitation study, NTG pigs housed with challenged NTG pigs exhibited significantly worse clinical symptoms than the other three in-contact groups. These results collectively suggest that HDAC6 overexpression enhances resistance to PRRSV infection both in vitro and in vivo. Our findings suggest the potential involvement of HDAC6 in the response to PRRSV, which will facilitate the development of novel therapies for PRRSV.
Highlights
Porcine reproductive and respiratory syndrome (PRRS) is one of the most severe infectious diseases that threaten the swine industry worldwide
Exogenous Histone deacetylase 6 (HDAC6) mRNA was detected in the TG pigs, and exogenous HDAC6 mRNA expression levels varied across the tissues examined in the TG pig (Fig 1C)
We found that pigs in TG pigs housed with challenged TG pigs (TG/TG) group did not show detectable PRRS virus (PRRSV) antibodies until 11 dpi and that PRRSV antibodies could be detected in other groups of housed pigs at 8 dpi (Fig 6E and S1 Table)
Summary
Porcine reproductive and respiratory syndrome (PRRS) is one of the most severe infectious diseases that threaten the swine industry worldwide. PRRS has caused substantial economic losses in swine production [1]. The causative agent of this syndrome is PRRS virus (PRRSV), which is classified in the family Arteriviridae within the order Nidovirales. PRRS is characterized by abortion, premature birth, and fetal death in pregnant sows and by severe respiratory failure in nursery pigs [3]. In 2006, the highly pathogenic PRRSV (HP-PRRSV) emerged in China, with a unique molecular hallmark of a discontinuous deletion of 30 amino acids in nonstructural protein 2 (Nsp). HP-PRRSV infection is characterized by high fever, high morbidity, and high mortality in pigs of all ages [4]. The emergence of HP-PRRSV exacerbates the international risks associated with PRRS
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