The genome of the simian and human malaria parasite Plasmodium knowlesi

Abstract

Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the 'kra' monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated, and it has a close phylogenetic relationship to Plasmodium vivax, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or 'hypnozoite' in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome and other sequenced Plasmodium genomes. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry.

Figure 1. Distribution of SICAvar genes, kir genes and telomere-like repeats on chromosomes 1 to 14 of P. knowlesi (H strain)

The positions of kir (shown in blue) and SICAvar (green) genes and gene fragments are shown on all 14 chromosomes. Interstitial telomeric sequences (GGGTT[T/C]A) are found surrounding kir and SICAvar genes (shown in red). The values along the right of each chromosome indicate the total sequence length in base pairs.

Figure 2. Structural organization of complete (full length) SICAvar genes in P. knowlesi (H strain)

Schematic view of the exon structure of type I and type II SICAvar genes. Exons are shown as red boxes with introns as joining lines.

Figure 3. Domain organization of complete (full-length) SICA and KIR proteins in P. knowlesi (H strain)

a, Domain organization of full-length SICA proteins. The number of different domains (SICA-α, SICA-β and SICA_C) is shown in parentheses. TM, transmembrane. b, Domain organization of full-length KIR proteins. c, Examples of an infected erythrocyte showing SICA and KIR proteins anchored to the surface in different combinations.

Figure 4. Matches to CD99 host sequences in P. knowlesi (H strain)

a, Seven KIRs show conserved matches to three different regions of CD99 (shown in red, blue and green). b, Schematic view of Macaca mulatta CD99, showing matches to different KIRs. The numbers represent the amino acid position. TM, transmembrane domain. The highlighted regions represent the summary of perfectly matched amino acid stretches in the CD99 extracellular domain to a subgroup of seven KIR proteins. c, Amino acid sequence of Macaca mulatta CD99, highlighting the summary of matches to KIRs. Amino acids corresponding to the transmembrane domain are underlined. The light-grey amino acids represent the transmembrane domain and the intracellular part of CD99. d, Comparison of the matches to Macaca fascicularis, African green monkey and human. Mismatches are highlighted in red. The asterisk refers to an additional host CD99 match in a KIR protein (PKH_031990) that did not satisfy the minimum length cutoff of 15 amino acids.