Abstract
Bovine papular stomatitis virus (BPSV) is a Parapoxvirus that induces acute pustular skin lesions in cattle and is transmissible to humans. Previous studies have shown that BPSV encodes a distinctive chemokine-binding protein (CBP). Chemokines are critically involved in the trafficking of immune cells to sites of inflammation and infected tissue, suggesting that the CBP plays a role in immune evasion by preventing immune cells reaching sites of infection. We hypothesised that the BPSV-CBP binds a wide range of inflammatory chemokines particularly those involved in BPSV skin infection, and inhibits the recruitment of immune cells from the blood into inflamed skin. Molecular analysis of the purified protein revealed that the BPSV-CBP is a homodimeric polypeptide with a MW of 82.4 kDa whilst a comprehensive screen of inflammatory chemokines by surface plasmon resonance showed high-affinity binding to a range of chemokines within the CXC, CC and XC subfamilies. Structural analysis of BPSV-CBP, based on the crystal structure of orf virus CBP, provided a probable explanation for these chemokine specificities at a molecular level. Functional analysis of the BPSV-CBP using transwell migration assays demonstrated that it potently inhibited chemotaxis of murine neutrophils and monocytes in response to CXCL1, CXCL2 as well as CCL2, CCL3 and CCL5 chemokines. In order to examine the effects of CBP in vivo, we used murine skin models to determine its impact on inflammatory cell recruitment such as that observed during BPSV infection. Intradermal injection of BPSV-CBP blocked the influx of neutrophils and monocytes in murine skin in which inflammation was induced with lipopolysaccharide. Furthermore, intradermal injection of BPSV-CBP into injured skin, which more closely mimics BPSV lesions, delayed the influx of neutrophils and reduced the recruitment of MHC-II+ immune cells to the wound bed. Our findings suggest that the CBP could be important in pathogenesis of BPSV infections.
Highlights
Bovine papular stomatitis virus (BPSV) is classified as a species within the Parapoxvirus (PPV) genus of the family Poxviridae [1] and induces acute pustular lesions on the muzzle, lips, oral mucosa and occasionally teats of cattle, in particular calves
The purified BPSV-chemokine-binding protein (CBP) was analysed by mass spectrometry, and multi-angle laser-light scattering size-exclusion chromatography (MALLSSEC), which revealed that the CBP forms a homodimer with a molecular mass of 82.4 kDa in solution (Fig 1B and 1C)
This study characterised the molecular and biological properties of the BPSV-CBP that is divergent at the amino acid level from its counterparts in the Parapoxvirus genus
Summary
Bovine papular stomatitis virus (BPSV) is classified as a species within the Parapoxvirus (PPV) genus of the family Poxviridae [1] and induces acute pustular lesions on the muzzle, lips, oral mucosa and occasionally teats of cattle, in particular calves. The pathology of BPSV infection is characterised by proliferative and erosive dermatitis, vacuolation and swelling of keratinocytes in the stratum spinosum, reticular degeneration and marked epidermal proliferation. Neutrophils migrate into areas of reticular degeneration and form microabscesses that subsequently rupture on the surface, giving rise to the pustular nature of the disease [2,3]. In the mild form of the disease, lesions are flat and typical inflammatory rings containing moderate infiltration of inflammatory cells have been observed around the involved areas [4,5]. The clinical course of the infection lasts several weeks and the virus can occasionally be transmitted to humans [2,4]
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