Genetically Attenuated, P36p-Deficient Malarial Sporozoites Induce Protective Immunity and Apoptosis of Infected Liver Cells

Immunization with Plasmodium sporozoites that have been attenuated by γ-irradiation or specific genetic modification can induce protective immunity against subsequent malaria infection. The mechanism of protection is only known for radiation-attenuated sporozoites, involving cell-mediated and humora...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 34; pp. 12194 - 12199
Main Authors:	van Dijk, Melissa R., Douradinha, Bruno, Franke-Fayard, Blandine, Heussler, Volker, van Dooren, Maaike W., van Schaijk, Ben, van Gemert, Geert-Jan, Sauerwein, Robert W., Mota, Maria M., Waters, Andrew P., Janse, Chris J.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 23-08-2005 National Acad Sciences
Subjects:	Animals Antigens, Protozoan - genetics Apoptosis Apoptosis - physiology Biological Sciences Blotting, Southern Caspase 3 Caspases Cells DNA Primers Female Genetic Vectors - genetics Genetics Hep G2 cells Hepatocytes Immune system Immunity Immunization Indoles Infections Liver Malaria - immunology Malaria Vaccines - genetics Malaria Vaccines - immunology Mice Mice, Inbred BALB C Mice, Inbred C57BL Parasite hosts Parasites Parasitism Plasmodium berghei Plasmodium berghei - genetics Plasmodium berghei - immunology Protozoan Proteins - genetics Reverse Transcriptase Polymerase Chain Reaction Sporozoites Sporozoites - genetics Sporozoites - immunology Transfection Vaccines, Attenuated - genetics
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Summary:	Immunization with Plasmodium sporozoites that have been attenuated by γ-irradiation or specific genetic modification can induce protective immunity against subsequent malaria infection. The mechanism of protection is only known for radiation-attenuated sporozoites, involving cell-mediated and humoral immune responses invoked by infected hepatocytes cells that contain longlived, partially developed parasites. Here we analyzed sporozoites of Plasmodium berghei that are deficient in P36p (p36p-), a member of the P48/45 family of surface proteins. P36p plays no role in the ability of sporozoites to infect and traverse hepatocytes, but p36p-sporozoites abort during development within the hepatocyte. Immunization with p36p-sporozoites results in a protective immunity against subsequent challenge with infectious wild-type sporozoites, another example of a specifically genetically attenuated sporozoite (GAS) conferring protective immunity. Comparison of biological characteristics of p36p-sporozoites with radiation-attenuated sporozoites demonstrates that liver cells infected with p36p-sporozoites disappear rapidly as a result of apoptosis of host cells that may potentiate the immune response. Such knowledge of the biological characteristics of GAS and their evoked immune responses are essential for further investigation of the utility of an optimized GAS-based malaria vaccine.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 To whom correspondence should be addressed. E-mail: waters@lumc.nl. M.R.v.D. and B.D. contributed equally to this work. This paper was submitted directly (Track II) to the PNAS office. Abbreviations: PV, parasitophorous vacuole; RAS, radiation-attenuated sporozoite; GAS, genetically attenuated sporozoite; SC, selection cassette. Edited by Louis H. Miller, National Institutes of Health, Bethesda, MD, and approved July 2, 2005 Author contributions: M.R.v.D., R.W.S., M.M.M., A.P.W., and C.J.J. designed research; M.R.v.D., B.D., M.W.v.D., B.v.S., G.-J.v.G., M.M.M., and C.J.J. performed research; B.F.-F. and V.H. contributed new reagents/analytic tools; M.R.v.D., B.D., B.v.S., M.M.M., and A.P.W. analyzed data; and M.R.v.D., M.M.M., A.P.W., and C.J.J. wrote the paper.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0500925102