Ticks produce highly selective chemokine binding proteins with antiinflammatory activity

Abstract

Bloodsucking parasites such as ticks have evolved a wide variety of immunomodulatory proteins that are secreted in their saliva, allowing them to feed for long periods of time without being detected by the host immune system. One possible strategy used by ticks to evade the host immune response is to produce proteins that selectively bind and neutralize the chemokines that normally recruit cells of the innate immune system that protect the host from parasites. We have identified distinct cDNAs encoding novel chemokine binding proteins (CHPBs), which we have termed Evasins, using an expression cloning approach. These CHBPs have unusually stringent chemokine selectivity, differentiating them from broader spectrum viral CHBPs. Evasin-1 binds to CCL3, CCL4, and CCL18; Evasin-3 binds to CXCL8 and CXCL1; and Evasin-4 binds to CCL5 and CCL11. We report the characterization of Evasin-1 and -3, which are unrelated in primary sequence and tertiary structure, and reveal novel folds. Administration of recombinant Evasin-1 and -3 in animal models of disease demonstrates that they have potent antiinflammatory properties. These novel CHBPs designed by nature are even smaller than the recently described single-domain antibodies (Hollinger, P., and P.J. Hudson. 2005. Nat. Biotechnol. 23:1126–1136), and may be therapeutically useful as novel antiinflammatory agents in the future.

Treatment with Evasin-3 Reduces Atherosclerotic Vulnerability for Ischemic Stroke, but Not Brain Injury in Mice

“…After having confirmed that CXC chemokines were markedly upregulated in both systemic circulation and atherosclerotic plaques of ApoE À / À mice, 23 we showed that their selective pharmacological inhibition was associated with the improvement of histologic parameters of plaque vulnerability. Similar results were obtained in a mouse model of rheumatoid arthritis, 8 a chronic treatment approach with low-dose Evasin-3 (5 daily injections of 1 mg/mouse per week for total 3 weeks of treatment) abrogated neutrophil infiltration and activation within the peripheral inflamed tissues (both carotid and aortic root atherosclerotic plaques). Importantly, Evasin-3-mediated inhibition of neutrophil activation was supported by the reduction in the intraplaque content of the neutrophilic granule enzyme MMP-9.…”

“…18 Treatment with Evasin-3 Does Not Affect CXC Chemokine Levels and Cerebral Injury in a Mouse Model of Cerebral Transient Focal Ischemia/Reperfusion Evasin-3 has been shown to mainly inhibit CXC chemokine bioactivity rather than tissue and serum levels. 8,9 In the stroke model, the bioactivity of each Evasin-3 batch was verified in vitro using mouse neutrophil chemotaxis assay before use (data not shown). To further confirm the neutralizing properties of Evasin-3, we also investigated if Evasin-3 treatment (a single intraperitoneal dose (10 mg/mouse), administered 5 minutes after the initiation of 45-minute cerebral ischemia) was associated with modifications in CXC chemokine levels in the brain 24 hours after stroke.…”

“…Since common inflammatory pathways have been recently indicated as promising pathophysiological targets for both prevention and treatment in ischemic stroke, 7 we focused on the pharmacological inhibition of CXC chemokines (mainly CXCL1 and CXCL2, which have been shown as the major leukocyte chemoattractants and activators). 8 In particular, we used the selective CXC chemokinebinding protein Evasin-3 (which has been recently shown to potently inhibit neutrophil-mediated cardiac injury after an acute myocardial infarction) 9 to abrogate CXC chemokine bioactivity in both prevention and treatment of ischemic stroke. Two validated mouse models (shear stress-induced carotid atherogenesis developing both vulnerable and stable plaques and transient focal cerebral ischemia) 10,11 were used to assess the potential benefits of Evasin-3 on neutrophil-mediated atherosclerotic plaque vulnerability and poststroke cerebral injury, respectively.…”

Ancestral reconstruction of tick lineages

“…Metastriates possess the evasins that belong to their own unique fold (Déruaz et al 2008;Frauenschuh et al 2007). Orthologs for these proteins have not been found in a N. namaqua salivary transcriptome (B.J.…”

The CCL3/Macrophage Inflammatory Protein-1α–Binding Protein Evasin-1 Protects from Graft-versus-Host Disease but Does Not Modify Graft-versus-Leukemia in Mice

“…A number of distinct chemokine-binding proteins (CBP) have been isolated from virus and other parasites, including ticks, that inhibit chemokine activity both in vitro and in vivo and play an important role in immune evasion (14)(15)(16)(17)(18)(19)(20). CBP derived from ticks, named evasins, appear to have unusually stringent chemokine selectivity, differentiating them from broader spectrum viral CBPs.…”