This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Labaied, M.
Right arrow Articles by Kappe, S. H. I.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Labaied, M.
Right arrow Articles by Kappe, S. H. I.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Charrin, S., Yalaoui, S., Bartosch, B., Cocquerel, L., Franetich, J.-F., Boucheix, C., Mazier, D., Rubinstein, E., Silvie, O. (2009). The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection. J. Biol. Chem. 284: 31572-31578 [Abstract] [Full Text]  
  • VanBuskirk, K. M., O'Neill, M. T., De La Vega, P., Maier, A. G., Krzych, U., Williams, J., Dowler, M. G., Sacci, J. B. Jr, Kangwanrangsan, N., Tsuboi, T., Kneteman, N. M., Heppner, D. G. Jr, Murdock, B. A., Mikolajczak, S. A., Aly, A. S. I., Cowman, A. F., Kappe, S. H. I. (2009). Preerythrocytic, live-attenuated Plasmodium falciparum vaccine candidates by design. Proc. Natl. Acad. Sci. USA 106: 13004-13009 [Abstract] [Full Text]  
  • Sarda, V., Kaslow, D. C., Williamson, K. C. (2009). Approaches to Malaria Vaccine Development Using the Retrospectroscope. Infect. Immun. 77: 3130-3140 [Full Text]  
  • Douradinha, B., Mota, M. M., Luty, A. J. F., Sauerwein, R. W. (2008). Cross-Species Immunity in Malaria Vaccine Development: Two, Three, or Even Four for the Price of One?. Infect. Immun. 76: 873-878 [Full Text]  
  • Purcell, L. A., Yanow, S. K., Lee, M., Spithill, T. W., Rodriguez, A. (2008). Chemical Attenuation of Plasmodium berghei Sporozoites Induces Sterile Immunity in Mice. Infect. Immun. 76: 1193-1199 [Abstract] [Full Text]  
  • Tarun, A. S., Peng, X., Dumpit, R. F., Ogata, Y., Silva-Rivera, H., Camargo, N., Daly, T. M., Bergman, L. W., Kappe, S. H. I. (2008). A combined transcriptome and proteome survey of malaria parasite liver stages. Proc. Natl. Acad. Sci. USA 105: 305-310 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»