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Infection and Immunity, August 2007, p. 3758-3768, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00225-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Plasmodium yoelii Sporozoites with Simultaneous Deletion of P52 and P36 Are Completely Attenuated and Confer Sterile Immunity against Infection{triangledown}

Mehdi Labaied,1 Anke Harupa,1 Ronald F. Dumpit,1 Isabelle Coppens,2 Sebastian A. Mikolajczak,1 and Stefan H. I. Kappe1,3*

Seattle Biomedical Research Institute, Seattle, Washington 98109,1 Department of Molecular Microbiology and Immunology and The Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205,2 Department of Pathobiology, University of Washington, Seattle, Washington 981953

Received 11 February 2007/ Returned for modification 18 March 2007/ Accepted 9 May 2007

Malaria infection starts when sporozoites are transmitted to the mammalian host during a mosquito bite. Sporozoites enter the blood circulation, reach the liver, and infect hepatocytes. The formation of a parasitophorous vacuole (PV) establishes their intracellular niche. Recently, two members of the 6-Cys domain protein family, P52 and P36, were each shown to play an important albeit nonessential role in Plasmodium berghei sporozoite infectivity for the rodent host. Here, we generated p52/p36-deficient Plasmodium yoelii parasites by the simultaneous deletion of both genes using a single genetic manipulation. p52/p36-deficient parasites exhibited normal progression through the life cycle during blood-stage infection, transmission to mosquitoes, mosquito-stage development, and sporozoite infection of the salivary glands. p52/p36-deficient sporozoites also showed normal motility and cell traversal activity. However, immunofluorescence analysis and electron microscopic observations revealed that p52/p36-deficient parasites did not form a PV within hepatocytes in vitro and in vivo. The p52/p36-deficient parasites localized as free entities in the host cell cytoplasm or the host cell nucleoplasm and did not develop as liver stages. Consequently, they did not cause blood-stage infections even at high sporozoite inoculation doses. Mice immunized with p52/p36-deficient sporozoites were completely protected against infectious sporozoite challenge. Our results demonstrate for the first time the generation of two-locus gene deletion-attenuated parasites that infect the liver but do not progress to blood-stage infection. The study will critically guide the design of Plasmodium falciparum live attenuated malaria vaccines.

* Corresponding author. Mailing address: Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109-5219. Phone: (206) 256-7205. Fax: (206) 256-7229. E-mail: stefan.kappe{at}sbri.org

{triangledown} Published ahead of print on 21 May 2007.

Editor: W. A. Petri, Jr.

Infection and Immunity, August 2007, p. 3758-3768, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00225-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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