FIG 2.

Circumsporozoite protein (CSP) of P. falciparum and its subdominant amino-terminal domain. (A) The sporozoite of P. falciparum is covered by CSP, in which a central repeat region is surrounded by distinct amino-terminal and carboxy-terminal domains. The repeat region is mainly composed of NANP tetrapeptide sequences (yellow) but starts with a single NPDP sequence (red) and also contains a few NVDP repeats (green) (47). While the repeat region is immunodominant, the amino-terminal region, which also is exposed on the sporozoite surface, is subdominant. In contrast, the carboxy-terminal region may be largely hidden in the intact CSP molecule. The immunodominant repeat region is the key component of the malaria vaccine RTS,S, as indicated. During an infection, CSP is cleaved at the RI site in the amino-terminal domain. Antibodies that bind close to this site (61) or to a junctional epitope located at the beginning of the repeat region (66–68) may protect against infection and may share the ability to block proteolysis at the RI site. Little is known about the structure of the subdominant amino-terminal domain, but it is noteworthy that the part located close to the repeats is charged (47), while the first 50 amino acid (aa) residues include 7 tyrosine residues. (B) Model for immunodominance and subdominance in CSP. The repeats of CSP may promote multipoint and high-avidity binding to cognate B cells, making the repeat region immunodominant by diverting the protein from B cells recognizing the nonrepeated domains, in particular, the surface-exposed amino-terminal domain (56, 57). The resulting subdominance of the amino-terminal domain may favor microbial virulence by allowing the microbe to evade potently protective antibodies directed against that domain. The limited protection conferred by antibodies to the repeats would be the price the microbe pays to achieve this result.