Abstract
Bovine respiratory syncytial virus (BRSV) is an important cause of respiratory disease in young cattle and is closely related to human RSV (HRSV), which causes severe respiratory disease in infants and the elderly. The RSV genome encodes a small hydrophobic (SH) protein with viroporin activity. Previous studies have shown that recombinant BRSV lacking the SH gene (rBRSVΔSH) is attenuated in the lungs, but not in the upper respiratory tract, of calves and mucosal vaccination with rBRSVΔSH induced long-lasting protective immunity. Attenuation of rBRSVΔSH may be due to the ability of this virus to induce an early innate response as rBRSVΔSH induces higher levels of pro-inflammatory cytokines than wild-type (wt) rBRSV. In this study, we investigated the effects of the BRSV SH protein on NF-κB p65 phosphorylation, a master step in the regulation of pro-inflammatory cytokines. Expression of SH resulted in the inhibition of NF-κB p65 phosphorylation in response to BRSV infection and extracellular lipopolysaccharide, and a reduction in the production of pro-inflammatory cytokines. In contrast, rBRSVΔSH does not inhibit NF-κB p65 phosphorylation in bovine antigen-presenting cells, including monocytes, macrophages and dendritic cells, resulting in increased expression of pro-inflammatory cytokines and increased activation of T cells compared to cells infected with wt BRSV. These findings highlight an important role for the BRSV SH protein in immune modulation.
Highlights
Bovine respiratory syncytial virus (BRSV) is a major cause of respiratory disease in young calves [1] and is closely related to human RSV (HRSV), which is the single most important cause of bronchiolitis and pneumonia in children under 5 years of age [2]
To determine if these two viruses differentially modulate the NF-kB signalling pathway, Madin–Darby bovine kidney (MDBK) and Vero cells were infected with rBRSV or rBRSVDSH in the presence or absence or rTNF-a and phosphorylation of NF-k B p65 was determined by Western blot
The rTNF-a mediated increase in p65 phosphorylation of MDBK and Vero cells was inhibited in cells infected with wt BRSV but not in cells infected with rBRSVDSH
Summary
Bovine respiratory syncytial virus (BRSV) is a major cause of respiratory disease in young calves [1] and is closely related to human RSV (HRSV), which is the single most important cause of bronchiolitis and pneumonia in children under 5 years of age [2]. Recombinant (r)BRSV in which the SH gene has been deleted (rBRSVDSH) induces higher levels of inflammatory cytokines IL-1b and TNF-a than wild-type (wt) virus in Madin–Darby bovine kidney (MDBK) cells and bovine monocytes [3]. The expression of many cytokines, including IL-1b and TNF-a, is regulated by the transcription factor NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells), which is activated by a series of phosphorylation and ubiquitinylation events resulting in phosphorylation of the p65 subunit and subsequent translocation to the nucleus where it helps to activate target gene transcription [5]. Antigen-presenting cells (APCs), including macrophages (Macs) and dendritic cells (DCs), are major sources of inflammatory cytokines, and NF-kB activation plays an important role in antigen presentation and T cell activation by APCs by regulating the level of expression of transporter associated with antigen processing 1 (TAP1) [6], major histocompatibility complex class I (MHC class I) [7] and co-stimulatory molecules such as CD40 and CD86 [8, 9]
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