Genetically attenuated, P36p-deficient malarial sporozoites induce protective immunity and apoptosis of infected liver cells.
Immunization with Plasmodium sporozoites that have been attenuated by gamma-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 long-lived, 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.
van Dijk
Melissa R
MR
Department of Parasitology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Douradinha
Bruno
B
Franke-Fayard
Blandine
B
Heussler
Volker
V
van Dooren
Maaike W
MW
van Schaijk
Ben
B
van Gemert
Geert-Jan
GJ
Sauerwein
Robert W
RW
Mota
Maria M
MM
Waters
Andrew P
AP
Janse
Chris J
CJ
D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics*; D017209:Apoptosis / Q000502:physiology*; D015139:Blotting, Southern; D053148:Caspase 3; D020169:Caspases; D017931:DNA Primers; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D022781:Hepatocytes; D007211:Indoles; D008288:Malaria / Q000276:immunology*; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000235:genetics / Q000276:immunology*; D015800:Protozoan Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D034101:Sporozoites / Q000235:genetics / Q000276:immunology*; D014162:Transfection; D014613:Vaccines, Attenuated / Q000235:genetics
D000953:Antigens, Protozoan; D017931:DNA Primers; D007211:Indoles; D017780:Malaria Vaccines; D015800:Protozoan Proteins; D014613:Vaccines, Attenuated; C007293:DAPI; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases