title: C3d binding to the circumsporozoite protein carboxy-terminus deviates immunity against malaria.
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.
authors.affiliation: Department of Immunology, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Elke S
authors.initials: ES
authors.lastname: Bergmann-Leitner
authors.forename: Sandra
authors.initials: S
authors.lastname: Scheiblhofer
authors.forename: Richard
authors.initials: R
authors.lastname: Weiss
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Duncan
authors.forename: Wolfgang W
authors.initials: WW
authors.lastname: Leitner
authors.forename: Defeng
authors.initials: D
authors.lastname: Chen
authors.forename: Evelina
authors.initials: E
authors.lastname: Angov
authors.forename: Farhat
authors.initials: F
authors.lastname: Khan
authors.forename: Jackie L
authors.initials: JL
authors.lastname: Williams
authors.forename: David B
authors.initials: DB
authors.lastname: Winter
authors.forename: Josef
authors.initials: J
authors.lastname: Thalhamer
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lyon
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D001483:Base Sequence; D015933:Complement C3d / Q000378:metabolism*; D008288:Malaria / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008969:Molecular Sequence Data; D010962:Plasmodium berghei / Q000276:immunology; D015800:Protozoan Proteins / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C041595:circumsporozoite protein, Protozoan; D015933:Complement C3d