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Infection and Immunity, March 2008, p. 1193-1199, Vol. 76, No. 3
0019-9567/08/$08.00+0     doi:10.1128/IAI.01399-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Chemical Attenuation of Plasmodium berghei Sporozoites Induces Sterile Immunity in Mice{triangledown}

Lisa A. Purcell,1,2 Stephanie K. Yanow,3 Moses Lee,4 Terry W. Spithill,1,5* and Ana Rodriguez2

Institute of Parasitology and Centre for Host-Parasite Interactions, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, Quebec, Canada H9X 3V9,1 Department of Medical Parasitology, New York University School of Medicine, 341 E. 25th Street, New York, New York 10010,2 Provincial Laboratory for Public Health, 8440 112th Street, Edmonton, Alberta, Canada T6G 2J2,3 Division of Natural and Applied Sciences and Department of Chemistry, Hope College, 35 E. 12th Street, Holland, Michigan 49423,4 School of Animal and Veterinary Sciences, Charles Sturt University, Wagga Wagga, Australia 26785

Received 17 October 2007/ Returned for modification 16 November 2007/ Accepted 19 December 2007

Radiation and genetic attenuation of Plasmodium sporozoites are two approaches for whole-organism vaccines that protect against malaria. We evaluated chemical attenuation of sporozoites as an alternative vaccine strategy. Sporozoites were treated with the DNA sequence-specific alkylating agent centanamycin, a compound that significantly affects blood stage parasitemia and transmission of murine malaria and also inhibits Plasmodium falciparum growth in vitro. Here we show that treatment of Plasmodium berghei sporozoites with centanamycin impaired parasite function both in vitro and in vivo. The infection of hepatocytes by sporozoites in vitro was significantly reduced, and treated parasites showed arrested liver stage development. Inoculation of mice with sporozoites that were treated in vitro with centanamycin failed to produce blood stage infections. Furthermore, BALB/c and C57BL/6 mice vaccinated with treated sporozoites were protected against subsequent challenge with wild-type sporozoites. Our findings demonstrate that chemically attenuated sporozoites could be a viable alternative for the production of an effective liver stage vaccine for malaria.

* Corresponding author. Present address: School of Animal and Veterinary Sciences, Charles Sturt University, Locked Bag 588, Wagga Wagga, NSW, Australia 2678. Phone: 61-2-6933 2439. Fax: 61-2-6933 2991. E-mail: tspithill{at}csu.edu.au

{triangledown} Published ahead of print on 3 January 2008.

Editor: W. A. Petri, Jr.

Infection and Immunity, March 2008, p. 1193-1199, Vol. 76, No. 3
0019-9567/08/$08.00+0     doi:10.1128/IAI.01399-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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