C3d binding to the circumsporozoite protein carboxy-terminus deviates immunity against malaria.
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.
Bergmann-Leitner
Elke S
ES
Department of Immunology, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
Scheiblhofer
Sandra
S
Weiss
Richard
R
Duncan
Elizabeth H
EH
Leitner
Wolfgang W
WW
Chen
Defeng
D
Angov
Evelina
E
Khan
Farhat
F
Williams
Jackie L
JL
Winter
David B
DB
Thalhamer
Josef
J
Lyon
Jeffrey A
JA
Tsokos
George C
GC
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
D000913:Antibodies, Protozoan; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C041595:circumsporozoite protein, Protozoan; D015933:Complement C3d