Ticks produce highly selective chemokine binding proteins with antiinflammatory activity.
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.
Déruaz
Maud
M
Merck Serono Geneva Research Centre, 1202 Geneva, Switzerland.
Frauenschuh
Achim
A
Alessandri
Ana L
AL
Dias
João M
JM
Coelho
Fernanda M
FM
Russo
Remo C
RC
Ferreira
Beatriz R
BR
Graham
Gerard J
GJ
Shaw
Jeffrey P
JP
Wells
Timothy N C
TN
Teixeira
Mauro M
MM
Power
Christine A
CA
Proudfoot
Amanda E I
AE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D025065:Borrelia burgdorferi; D018925:Chemokines / Q000378:metabolism*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D011485:Protein Binding; D019707:Receptors, Chemokine / Q000378:metabolism*; D048508:Rhipicephalus sanguineus; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D018925:Chemokines; D018076:DNA, Complementary; C523601:Evasin-1, Rhipicephalus sanguineus; D019707:Receptors, Chemokine