Structure of the Gene Encoding the Immunodominant Surface Antigen on the Sporozoite of the Human Malaria Parasite Plasmodium falciparum

Abstract

The gene for the circumsporozoite (CS) protein of Plasmodium falciparum has been cloned and its nucleotide sequence determined. The gene encodes a protein of 412 amino acids as deduced from the nucleotide sequence. The protein contains 41 tandem repeats of a tetrapeptide, 37 of which are Asn-Ala-Asn-Pro and four of which are Asn-Val-Asp-Pro. Monoclonal antibodies against the CS protein of Plasmodium falciparum were inhibited from binding to the protein by synthetic peptides of the repeat sequence. The CS protein of Plasmodium falciparum and the CS protein of a simian malaria parasite, Plasmodium knowlesi, have two regions of homology, one of which is present on either side of the repeat. One region contains 12 of 13 identical amino acids. Within the nucleotide sequence of this region, 25 of 27 nucleotides are conserved. The conservation of these regions in parasites widely separated in evolution suggests that they may have a function such as binding to liver cells and may represent an invariant target for immunity.

Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes.

“…Lactoferrin (aa [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] CAVS QPETKCFQRNMRKI/R yoelii CS, apoE, and lactoferrin. Boldface italics indicate amino acid residues of CS protein required for binding to HSPGs (22).…”

“…Heparinase treatment of liver sections that have been incubated with CS, and other in vitro experiments using hepatocytes and HepG2 cells as targets, demonstrate that CS binds to HSPGs (19,20). The proteoglycan-binding portion of CS (19,21) is region II-plus (22), a stretch of amino acids highly conserved in all species of malaria parasites (23). The region II-plus motif is also found in thrombospondin-related adhesive protein/sporozoite surface protein 2 (TRAP/ SSP2), another surface protein of malaria sporozoites (24,25) that binds to cell surface HSPGs (26,27).…”

Malaria: The end of the beginning

“…In the early 1980s antibodies against the sporozoites were used by researchers at the National Institutes of Health and WRAIR to identify the 'circumsporozoite' protein (CSP) and clone the relevant gene 3 . Working with WRAIR, the labs of what was then SmithKline Beckman in Philadelphia, Pennsylvania, zeroed in on a repeating pattern in the protein that seemed to be a major target of antibodies.…”

Cytotoxic T Lymphocytes in Humans Exposed to Plasmodium falciparum by Immunization or Natural Exposure

“…They have mapped the epitope to residues 330 339 (KIQNSLSTEW) of the NF54/3D7 sequence of the PfCSP (CASPERS et al 1989;CAMPBELL 1989) and demonstrated that this peptide is recognized in the context of HLA DR7. This epitope corresponds to amino acids 337 346 of the 7G8 sequence of the PfCSP (DAME et al 1984) and is found in a polymorphic region of the CS protein (Table 3; LOCKYER et al 1989;DOOLAN et al 1992;SHI et al 1992). It has therefore been suggested that, as for the CD8' CTL epitope described above, the variation in this region is a result of immune selection.…”