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J. Biol. Chem., Vol. 282, Issue 40, 29256-29263, October 5, 2007

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Selective Cysteine Protease Inhibition Contributes to Blood-feeding Success of the Tick Ixodes scapularis^*

Michalis Kotsyfakis, Shahid Karim, John F. Andersen, Thomas N. Mather, and José M. C. Ribeiro¹

From the Vector Biology Section, Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Rockville, Maryland 20852 and the Center for Vector-Borne Disease, University of Rhode Island, Kingston, Rhode Island 02881

Ixodes scapularis is the main vector of Lyme disease in the eastern and central United States. Tick salivary secretion has been shown as important for both blood-meal completion and pathogen transmission. Here we report a duplication event of cystatin genes in its genome that results in a transcription-regulated boost of saliva inhibitory activity against a conserved and relatively limited number of vertebrate papain-like cysteine proteases during blood feeding. We further show that the polypeptide products of the two genes differ in their binding affinity for some enzyme targets, and they display different antigenicity. Moreover, our reverse genetic approach employing RNA interference uncovered a crucial mediation in tick-feeding success. Given the role of the targeted enzymes in vertebrate immunity, we also show that host immunomodulation is implicated in the deleterious phenotype of silenced ticks making I. scapularis cystatins attractive targets for development of antitick vaccines.

Received for publication, April 13, 2007 , and in revised form, July 12, 2007.

^* This work was supported by Division of Intramural Research, NIAID, National Institutes of Health Grant 5R01AI037230 (to T. N. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 301-496-9389; Fax: 301-480-2571; E-mail: jribeiro{at}niaid.nih.gov.

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