C3d binding to the circumsporozoite protein carboxy-terminus deviates immunity against malaria

• Published in: International immunology 2005-03, Vol.17 (3), p.245-255
• Main Authors: Bergmann-Leitner, Elke S., Scheiblhofer, Sandra, Weiss, Richard, Duncan, Elizabeth H., Leitner, Wolfgang W., Chen, Defeng, Angov, Evelina, Khan, Farhat, Williams, Jackie L., Winter, David B., Thalhamer, Josef, Lyon, Jeffrey A., Tsokos, George C.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Protozoan - immunology; APC antigen-presenting cell; Base Sequence; complement; Complement C3d - metabolism; CR2 complement receptor 2; CSP circumsporozoite protein; DOC day-of-challenge; DTT dithiothreitol; GPI glycosyl-phosphatidylinositol; GSH glutathione; GST glutathione-S-transferase; HEL hen egg lysozyme; host defense; IFA immunofluorescence assay; Malaria; Malaria - immunology; Malaria - prevention & control; Mice; Molecular Sequence Data; Plasmodium berghei; Plasmodium berghei - immunology; Protozoan Proteins - immunology; Protozoan Proteins - metabolism; Protozoan Proteins - therapeutic use; Recombinant Proteins - metabolism; RT room temperature; Spleen - cytology; Spleen - immunology; T lymphocytes; Th2 Cells - immunology; TPA tissue plasminogen activator
• ISSN: 0953-8178; 1460-2377; 1460-2377
• DOI: 10.1093/intimm/dxh205

The immunogenicity of recombinant protein or anti-viral DNA vaccines can be significantly improved by the addition of tandem copies of the complement fragment C3d. We sought to determine if the efficacy of a circumsporozoite protein (CSP)-based DNA vaccine delivered to mouse skin by gene gun was improved by using this strategy. Instead, we found that C3d suppressed the protective immunity against Plasmodium berghei malaria infection and deviated immunity, most notably by suppressing the induction of antibodies specific for the CSP C-terminal flanking sequence and by suppressing the induction of CSP-specific IL-4-producing spleen cells. We further showed that C3d bound to the C-terminal flanking sequence of the CSP, which may explain the immune deviation observed in CS/C3d chimeric antigen. We have thus identified C3d-mediated epitope masking and shifting of both the humoral and cellular immune responses as a potential novel escape mechanism, which plasmodia may use to divert the induction of protective immunity.