International Immunology Advance Access originally published online on February 14, 2005
International Immunology 2005 17(3):245-255; doi:10.1093/intimm/dxh205
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C3d binding to the circumsporozoite protein carboxy-terminus deviates immunity against malaria
1 Department of Immunology, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
2 Immunology Group, Institute of Chemistry and Biochemistry, University of Salzburg, Salzburg, Austria
3 Dermatology Branch, NCI/NIH, Bethesda, MD 20892, USA
4 Department of Entomology and 5 Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD, 20910 USA
Correspondence to: G. C. Tsokos; E-mail: gtsokos{at}usuhs.mil
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.
Keywords: complement, host defense, malaria, T lymphocytes
* These authors contributed equally to this study
Transmitting editor: T. F. Tedder
The authors' views are personal and are not to be construed as official policy of the Department of Defense or the U.S. Army. Research was conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 1996 edition. All procedures were reviewed and approved by the Institute's Animal Care and Use Committee, and performed in a facility accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International.
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