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Infection and Immunity, April 2004, p. 2214-2221, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2214-2221.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Molecular Characterization of Ancylostoma ceylanicum Kunitz-Type Serine Protease Inhibitor: Evidence for a Role in Hookworm-Associated Growth Delay

Daniel Chu,1 Richard D. Bungiro,1 Maureen Ibanez,1 Lisa M. Harrison,1 Eva Campodonico,1 Brian F. Jones,1 Juliusz Mieszczanek,1,2 Petr Kuzmic,3 and Michael Cappello1*

Child Health Research Center, Departments of Pediatrics and Epidemiology & Public Health, Yale School of Medicine, New Haven, Connecticut,1 Department of Parasitology, Warsaw Agricultural University, Warsaw, Poland,2 BioKin Ltd., Pullman, Washington3

Received 26 November 2003/ Returned for modification 15 December 2003/ Accepted 24 December 2003

Hookworm infection is a major cause of iron deficiency anemia and malnutrition in developing countries. The Ancylostoma ceylanicum Kunitz-type inhibitor (AceKI) is a 7.9-kDa broad-spectrum inhibitor of trypsin, chymotrypsin, and pancreatic elastase that has previously been isolated from adult hookworms. Site-directed mutagenesis of the predicted P1 inhibitory reactive site amino acid confirmed the role of Met26 in mediating inhibition of the three target serine proteases. By using reverse transcription-PCR, it was demonstrated that the level of AceKI gene expression increased following activation of third-stage larvae with serum and that the highest level of expression was reached in the adult stage of the parasite. Immunohistochemistry studies performed with polyclonal immunoglobulin G raised against recombinant AceKI showed that the inhibitor localized to the subcuticle of the adult hookworm, suggesting that it has a potential in vivo role in neutralizing intestinal proteases at the surface of the parasite. Immunization with recombinant AceKI was shown to confer partial protection against hookworm-associated growth delay without a measurable effect on anemia. Taken together, the data suggest that AceKI plays a role in the pathogenesis of hookworm-associated malnutrition and growth delay, perhaps through inhibition of nutrient absorption in infected hosts.

* Corresponding author. Mailing address: Yale Child Health Research Center, P.O. Box 208081, New Haven, CT 06520-8081. Phone: (203) 737-4320. Fax: (203) 737-5972. E-mail: michael.cappello{at}yale.edu.

Editor: W. A. Petri, Jr.

Infection and Immunity, April 2004, p. 2214-2221, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2214-2221.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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