The chemokine-binding protein encoded by the poxvirus orf virus inhibits recruitment of dendritic cells to sites of skin inflammation and migration to peripheral lymph nodes

Abstract

SummaryOrf virus (ORFV) is a zoonotic parapoxvirus that induces acute pustular skin lesions in sheep and humans. ORFV can reinfect its host and the discovery of several secreted immune modulatory factors that include a chemokine-binding protein (CBP) may explain this phenomenon. Dendritic cells (DC) are professional antigen presenting cells that induce adaptive immunity and their recruitment to sites of infection in skin and migration to peripheral lymph nodes is critically dependent on inflammatory and constitutive chemokine gradients respectively. Here we examined whether ORFV-CBP could disable these gradients using mouse models. Previously we established that ORFV-CBP bound murine inflammatory chemokines with high affinity and here we show that this binding spectrum extends to constitutive chemokines CCL19 and CCL21. Using cell-based chemotaxis assays, ORFV-CBP inhibited the movement of both immature and mature DC in response to these inflammatory and constitutive chemokines respectively. Moreover in C57BL/6 mice, intradermally injected CBP potently inhibited the recruitment of blood-derived DC to lipopolysaccharide-induced sites of skin inflammation and inhibited the migration of ex vivo CpG-activated DC to inguinal lymph nodes. Finally we showed that ORFV-CBP completely inhibited T responsiveness in the inguinal lymph nodes using intradermally injected DC pulsed with ovalbumin peptide and transfused transgenic T cells.

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.…”

“…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.…”

“…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.…”

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.…”