Microbiol. on the vascular lining (33). This adherence enables the parasite to escape clearance in the spleen and can be detrimental to the human host by facilitating high parasite growth rates and unchecked and harmful inflammation (8). Individuals living in areas where is endemic acquire natural protective immunity from malaria over a period of several years by a gradual acquisition of specific immunoglobulin G (IgG) against different VSA (reviewed in references 7 and 12). PfEMP1 is the best-characterized VSA (40), and antibodies to these molecules have been associated with protection against malaria in both children (20) and pregnant women (29). PfEMP1 molecules are encoded by the gene family, comprising 40 to 60 highly diverse genes per haploid genome (3, 35, 40). The genome of the clone 3D7 encodes 59 full-length genes, which can be grouped into three major groups (A, B, and C) and two intermediate groups (B/A and B/C) on the basis of Angiotensin II chromosomal location, direction of transcription with respect to Angiotensin II chromosome telomeres, domain structure of the encoded proteins, and sequence similarities in coding and noncoding regions (15, 18). The extracellular and variable sequence of PfEMP1 comprises four different domain types: the N-terminal segment, the C2, the cysteine-rich interdomain region (CIDR), and the Duffy binding-like (DBL) domains (9, 40). The CIDR domains group as three (, , and ) and the DBL domains as seven (, , Rabbit Polyclonal to HTR2C , , ?, , and x) distinct sequence classes (3, 36, 40). Groups A and B/A make up the largest PfEMP1s, with a 7- to 10-domain structure, which is different from the 4-domain-type structure predominant of groups B, B/C, and C (18). Several studies have demonstrated that parasites causing severe malaria in young children who have little or no protective immunity tend to express VSA linked to severe malaria (VSASM) that are serologically distinct from those expressed by parasites causing uncomplicated and subclinical infection in older, more immune individuals (6, 24). The VSASM appear to be serologically more conserved and cross-reactive than VSA expressed during uncomplicated malaria infections (VSAUM) (25), consistent with the finding that immunity to severe malaria is acquired more rapidly than immunity to uncomplicated disease (28). We have previously established a link between expression of group A or B/A (here collectively named category A) PfEMP1 and the VSASM phenotype and a link between expression of group B, B/C, or C (here collectively named category Angiotensin II non-A) PfEMP1 and the VSAUM phenotype (13). The serological diversity among parasites expressing VSASM is lower than that among parasites expressing VSAUM, possibly because of functional constraints (18), and this suggests that category A PfEMP1 molecules would be more likely to share cross-reactive antibody epitopes than molecules not belonging to this category. The sequence similarity between different PfEMP1 domains varies, but it is generally limited and amino acid alignments will often be characterized by relatively short runs of conserved residues interrupted by much longer stretches of high sequence diversity (36, 41). Protective immunity against Angiotensin II malaria could be acquired either as individuals build a broad repertoire of antibodies against polymorphic PfEMP1 epitopes or by slow acquisition of antibodies against conserved PfEMP1 epitopes. Previously, some reports have indicated that agglutinating VSA antibodies do not seem to be directed against conserved epitopes (22), while others have shown that some cross-reactivity must exist since a Angiotensin II single infection is capable of inducing antibodies cross-reacting with VSA expressed on heterologous parasite isolates.