title: An immunologically cryptic epitope of Plasmodium falciparum circumsporozoite protein facilitates liver cell recognition and induces protective antibodies that block liver cell invasion.
abstract: Circumsporozoite, a predominant surface protein, is involved in invasion of liver cells by Plasmodium sporozoites, which leads to malaria. We have previously reported that the amino terminus region (amino acids 27-117) of P. falciparum circumsporozoite protein plays a critical role in the invasion of liver cells by the parasite. Here we show that invasion-blocking antibodies are induced by a polypeptide encoding these 91 amino acids, only when it is presented in the absence of the rest of the protein. This suggests that when present in the whole protein, the amino terminus remains immunologically cryptic. A single reactive epitope was identified and mapped to a stretch of 21 amino acids from position 93 to 113. The epitope is configurational in nature, since its recognition was affected by deleting as little as 3 amino acids from either end of the 21-residue peptide. Lysine 104, the only known polymorphic position in the epitope, affected its recognition by the antibodies, and its conversion to leucine in the protein led to a substantial loss of binding activity of the protein to the hepatocytes. This indicated that in the protein, the epitope serves as a binding ligand and facilitates the interaction between sporozoite and hepatic cells. When considered along with the observation that in its native state this motif is immunologically unresponsive, we suggest that hiding functional moieties of the protein from the immune system is an evasion strategy to preserve liver cell binding function and may be of importance in designing anti-sporozoite vaccines.
authors.affiliation: Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA. Rathore@vbi.vt.edu
authors.forename: Dharmendar
authors.initials: D
authors.lastname: Rathore
authors.forename: Rana
authors.initials: R
authors.lastname: Nagarkatti
authors.forename: Dewal
authors.initials: D
authors.lastname: Jani
authors.forename: Rana
authors.initials: R
authors.lastname: Chattopadhyay
authors.forename: Patricia
authors.initials: P
authors.lastname: de la Vega
authors.forename: Sanjai
authors.initials: S
authors.lastname: Kumar
authors.forename: Thomas F
authors.initials: TF
authors.lastname: McCutchan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006528:Carcinoma, Hepatocellular; D005455:Fluorescent Antibody Technique; D006801:Humans; D008099:Liver / Q000276:immunology* / Q000469:parasitology*; D008113:Liver Neoplasms; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010963:Plasmodium falciparum / Q000737:chemistry / Q000276:immunology / Q000472:pathogenicity; D016133:Polymerase Chain Reaction; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D034101:Sporozoites / Q000254:growth & development / Q000472:pathogenicity; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan