Orf virus-encoded chemokine-binding protein is a potent inhibitor of inflammatory monocyte recruitment in a mouse skin model

Abstract

The parapoxvirus orf virus causes pustular dermatitis in sheep and is transmissible to humans. The virus encodes a secreted chemokine-binding protein (CBP). We examined the ability of this protein to inhibit migration of murine monocytes in response to CC inflammatory chemokines, using chemotaxis assays, and its effects on monocyte recruitment into the skin, using a mouse model in which inflammation was induced with bacterial lipopolysaccharide. CBP was shown to bind murine chemokines CCL2, CCL3 and CCL5 with high affinity by surface plasmon resonance and it completely inhibited chemokine-induced migration of monocytes at a CBP : chemokine molar ratio of 4 : 1. In the mouse, low levels of CBP potently inhibited the recruitment of Gr-1 + / CD11b + monocytes to the site of inflammation in the skin but had little effect on neutrophil recruitment, suggesting that this factor plays a role in disrupting chemokine-induced recruitment of specific immune cell types to infection sites.

Effect of a Broad-Specificity Chemokine-Binding Protein on Brain Leukocyte Infiltration and Infarct Development

“…The chemokine-binding spectrum and affinities of the BPSV CBP were consistent with those reported for the CBP from its fellow parapoxvirus, orf virus. [13][14][15]18 After establishing the ability of the CBP to inhibit a broad spectrum of chemokines, we investigated its efficacy in vivo. We found that intravenous administration of the CBP after transient cerebral ischemia largely prevented stroke-induced increases in circulating levels of key chemokines in association with milder neurological deficit at 24 hours.…”

“…The CBP from orf virus, the type species of the parapoxvirus genus, binds a range of CC, CXC, and C chemokines with high affinity and can neutralize the activity of CC chemokines in vitro and in vivo. [13][14][15]18 Publication of the complete genome sequence of another parapoxvirus, BPSV strain AR-02 revealed an equivalent CBP ≈24 kb from the right terminus of the genome. 16 We therefore sequenced the corresponding region in the BamHI A fragment of the genome from BPSV strain V660 and identified an equivalent CBP.…”

“…11 Many viruses secrete proteins that bind chemokines as a means of evading the host immune system and ensuring their own survival. 12 Recently, a novel type of chemokine-binding protein (CBP) has been identified from orf virus, [13][14][15] and fellow parapoxviruses, bovine papular stomatitis virus (BPSV), and pseudocowpox virus. 16,17 This CBP shows high-affinity binding for both human and mouse CC, CXC, and C chemokines and has been demonstrated to prevent inflammatory monocyte recruitment to the skin and to block dendritic cell trafficking to peripheral lymph nodes.…”

“…16,17 This CBP shows high-affinity binding for both human and mouse CC, CXC, and C chemokines and has been demonstrated to prevent inflammatory monocyte recruitment to the skin and to block dendritic cell trafficking to peripheral lymph nodes. [13][14][15]18 Because of its capacity to bind 3 classes of chemokine and to impair leukocyte trafficking in vivo, the parapoxvirus CBP represents a powerful tool with which to target a broad range of chemokines and dissect their role in the pathogenesis of diseases driven by inflammation. Thus, here we have tested the hypothesis that acute systemic administration of CBP after cerebral ischemia-reperfusion in mice may reduce plasma chemokine levels, leukocyte infiltration, and infarct development.…”

Rodent Herpesvirus Peru Encodes a Secreted Chemokine Decoy Receptor

“…Myxoma viruses deficient in M-T1(vCCI) have a subtle phenotype, with an increase in leukocyte infiltration but no significant difference in disease progression or mortality (18,25). In addition, mouse studies of ORF virus infection, a zoonotic parapoxvirus, shown to encode vCCI-like chemokine binding protein (26), demonstrated that ORF virus (ORFV) vCCI blocks the recruitment of immature and mature dendritic cells to the skin and lymph nodes and inhibits T cell responsiveness in lymph nodes (26,27). The role of herpesvirusencoded chemokine binding proteins in pathogenesis and immune modulation remains poorly understood, in part due to lack of the appropriate experimental host.…”