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International Immunology Advance Access published online on February 14, 2005
International Immunology, doi:10.1093/intimm/dxh205
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Received May 18, 2004
Accepted December 6, 2004

Article

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

Elke S. Bergmann-Leitner 1 *, Sandra Scheiblhofer 2 *, Richard Weiss 2, Elizabeth H. Duncan 1, Wolfgang W. Leitner 3, Defeng Chen 1, Evelina Angov 1, Farhat Khan 1, Jackie L. Williams 4, David B. Winter 5, Josef Thalhamer 2, Jeffrey A. Lyon 1, and George C. Tsokos 5*

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, Walter Reed Army Institute of Research, Silver Spring, MD, 20910 USA
5 Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, MD, 20910 USA

* To whom correspondence should be addressed.
George C. Tsokos, E-mail: gtsokos{at}usuhs.mil


  Abstract

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


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