Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response.
The 19 kDa C-terminal fragment of the malaria parasite merozoite surface protein 1 (MSP1(19)) is a leading malaria vaccine candidate. In rodents, high antibody levels to this protein confer protective immunity, and can be generated by immunization with the antigen in adjuvants. In natural human infections, however, MSP1(19)-specific antibody responses can be short-lived and comparatively low, despite repeated exposure to infection. The tightly folded structure of MSP1(19) is stabilized by five or six disulfide bonds. These bonds impede antigen processing and, thereby, may affect the generation of CD4+ T cells providing help for B cells. Asparagine endopeptidase could digest unfolded, but not native MSP1(19) in vitro. Immunization with unfolded MSP1(19) resulted in a faster antibody response, and a combination of unfolded and native MSP1(19) increased antibody responses to the native form. Immunization with either form of the antigen activated similar numbers of CD4+ T cells, but, unlike the antibody response, CD4+ T cells immunized with one form of MSP119 were able to respond in vitro to the other form of the protein. Although the reduced form of MSP1(19) does not induce protective antibodies, our data suggest that inclusion of unfolded protein may improve the efficacy of MSP1(19) as a vaccine.
Hensmann
Meike
M
Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, GB.
Li
Ching
C
Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, GB.
Moss
Catherine
C
Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, GB.
Lindo
Viv
V
Department of Biochemistry, Wellcome Trust Biocentre, University of Dundee, Dundee, GB.
Greer
Fiona
F
M-Scan Ltd., Wokingham, GB.
Watts
Colin
C
Department of Biochemistry, Wellcome Trust Biocentre, University of Dundee, Dundee, GB.
Ogun
Solabomi A
SA
Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, GB.
Holder
Anthony A
AA
Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, GB.
Langhorne
Jean
J
Division of Parasitology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, GB.
D000595:Amino Acid Sequence; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood*; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004220:Disulfides; D005260:Female; D008247:Lysosomes / Q000201:enzymology; D008288:Malaria / Q000276:immunology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000737:chemistry* / Q000276:immunology*; D020066:Merozoite Surface Protein 1 / Q000737:chemistry* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016788:Plasmodium chabaudi / Q000737:chemistry; D010967:Plasmodium yoelii / Q000737:chemistry; D016415:Sequence Alignment
D000913:Antibodies, Protozoan; D004220:Disulfides; D017780:Malaria Vaccines; D020066:Merozoite Surface Protein 1; D003546:Cysteine Endopeptidases; C447421:asparaginyl endopeptidase, lysosomal