Disulfide bonds in merozoite surface protein 1 of the malaria parasite impede efficient antigen processing and affect the in vivo antibody response

• Published in: European journal of immunology 2004-03, Vol.34 (3), p.639-648
• Main Authors: Hensmann, Meike, Li, Ching, Moss, Catherine, Lindo, Viv, Greer, Fiona, Watts, Colin, Ogun, Solabomi A., Holder, Anthony A., Langhorne, Jean
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies, Protozoan - blood; Antigen Presentation; Antigen processing; asparagine endopeptidase; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cysteine Endopeptidases - metabolism; Disulfides; Female; Lysosomes - enzymology; Malaria; Malaria - immunology; Malaria - prevention & control; Malaria Vaccines - chemistry; Malaria Vaccines - immunology; Merozoite; merozoite surface protein 1; Merozoite Surface Protein 1 - chemistry; Merozoite Surface Protein 1 - immunology; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Plasmodium chabaudi - chemistry; Plasmodium yoelii - chemistry; Sequence Alignment; Vaccine
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200324514

The 19 kDa C‐terminal fragment of the malaria parasite merozoite surface protein 1 (MSP119) 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, MSP119‐specific antibody responses can be short‐lived andcomparatively low, despite repeated exposure to infection. The tightly folded structure of MSP119 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 MSP119 in vitro. Immunization with unfolded MSP119 resulted in a faster antibody response, and a combination of unfolded and native MSP119 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 MSP119 does not induce protective antibodies, our data suggest that inclusion of unfolded protein may improve the efficacy of MSP119 as a vaccine. See correction http://dx.doi.org/10.1002/eji.200490004