The complexity of protective immunity against liver-stage malaria.
Sterile protective immunity against challenge with Plasmodium spp. sporozoites can be induced in multiple model systems and humans by immunization with radiation-attenuated Plasmodium spp. sporozoites. The infected hepatocyte has been established as the primary target of this protection, but the underlying mechanisms have not been completely defined. Abs, CD8+ T cells, CD4+ T cells, cytokines (including IFN-gamma and IL-12), and NO have all been implicated as critical effectors. Here, we have investigated the mechanisms of protective immunity induced by immunization with different vaccine delivery systems (irradiated sporozoites, plasmid DNA, synthetic peptide/adjuvant, and multiple Ag peptide) in genetically distinct inbred strains, genetically modified mice, and outbred mice. We establish that there is a marked diversity of T cell-dependent immune responses that mediate sterile protective immunity against liver-stage malaria. Furthermore, we demonstrate that distinct mechanisms of protection are induced in different strains of inbred mice by a single method of immunization, and in the same strain by different methods of immunization. These data underscore the complexity of the murine host response to a parasitic infection and suggest that an outbred human population may behave similarly. Data nevertheless suggest that a pre-erythrocytic-stage vaccine should be designed to induce CD8+ T cell- and IFN-gamma-mediated immune responses and that IFN-gamma responses may represent an in vitro correlate of pre-erythrocytic-stage protective immunity.
Doolan
D L
DL
Malaria Program, Naval Medical Research Center, Silver Spring, MD 20910, USA. dooland@nmripo.nmri.nnmc.navy.mil
Hoffman
S L
SL
D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D053222:Fas Ligand Protein; D005260:Female; D053804:Granzymes; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D007110:Immunity, Active; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000502:physiology; D008024:Ligands; D008099:Liver / Q000276:immunology* / Q000469:parasitology*; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D008288:Malaria / Q000201:enzymology / Q000276:immunology* / Q000469:parasitology*; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D054353:Perforin; D010967:Plasmodium yoelii / Q000254:growth & development / Q000276:immunology* / Q000528:radiation effects; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000502:physiology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism
D015415:Biomarkers; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006183:H-2 Antigens; D008024:Ligands; D017780:Malaria Vaccines; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019444:Vaccines, DNA; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases