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Antimicrobial Agents and Chemotherapy, February 2007, p. 679-688, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.01059-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Cysteine Protease Inhibitors Block Toxoplasma gondii Microneme Secretion and Cell Invasion{triangledown}

Chin Fen Teo,1,{dagger} Xing Wang Zhou,1,{ddagger} Matthew Bogyo,2 and Vern B. Carruthers1,§*

Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, Maryland 21205,1 Department of Pathology, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, California 943052

Received 22 August 2006/ Returned for modification 13 October 2006/ Accepted 26 November 2006

Toxoplasma gondii enters host cells via an active, self-driven process to fulfill its need for intracellular replication and survival. Successful host cell invasion is governed by sequential release of secretory proteins from three specialized organelles, including the micronemes, which contribute adhesive proteins necessary for parasite attachment and penetration. Cumulative evidence from studies of Trypanosoma species and malaria parasites has shown that cysteine protease inhibitors represent potent anti-parasitic agents capable of curing infections in vivo. In this study, we screened a series of selective cysteine protease inhibitors for their effects on T. gondii cell invasion. Two of these compounds, morpholinourea-leucyl-homophenolalaninyl-phenyl-vinyl-sulfone and N-benzoxycarbonyl-(leucyl)3-phenyl-vinyl-sulfone, impaired T. gondii invasion and gliding motility at low-micromolar concentrations. Unexpectedly, these inhibitors did not affect surface proteolysis of microneme products but instead impaired an earlier step by precluding the secretion of microneme-derived adhesins to the parasite surface. Our findings suggest that cysteine protease activity is required for microneme secretion and cell invasion by T. gondii.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Michigan School of Medicine, 1150 W. Medical Center Drive, Ann Arbor, MI 48109. Phone: (734) 763-2081. Fax: (734) 764-3562. E-mail: vcarruth{at}umich.edu.

{triangledown} Published ahead of print on 4 December 2006.

{dagger} Present address: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602.

{ddagger} Present address: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201.

§ Present address: Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109.

Antimicrobial Agents and Chemotherapy, February 2007, p. 679-688, Vol. 51, No. 2
0066-4804/07/$08.00+0     doi:10.1128/AAC.01059-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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