Plasmodium knowlesi:a superbin vivononhuman primate model of antigenic variation in malaria

Abstract

SUMMARYAntigenic variation in malaria was discovered in Plasmodium knowlesi studies involving longitudinal infections of rhesus macaques (M. mulatta). The variant proteins, known as the P. knowlesi Schizont Infected Cell Agglutination (SICA) antigens and the P. falciparum Erythrocyte Membrane Protein 1 (PfEMP1) antigens, expressed by the SICAvar and var multigene families, respectively, have been studied for over 30 years. Expression of the SICA antigens in P. knowlesi requires a splenic component, and specific antibodies are necessary for variant antigen switch events in vivo. Outstanding questions revolve around the role of the spleen and the mechanisms by which the expression of these variant antigen families are regulated. Importantly, the longitudinal dynamics and molecular mechanisms that govern variant antigen expression can be studied with P. knowlesi infection of its mammalian and vector hosts. Synchronous infections can be initiated with established clones and studied at multi-omic levels, with the benefit of computational tools from systems biology that permit the integration of datasets and the design of explanatory, predictive mathematical models. Here we provide an historical account of this topic, while highlighting the potential for maximizing the use of P. knowlesi – macaque model systems and summarizing exciting new progress in this area of research.

Distinct amino acid and lipid perturbations characterize acute versus chronic malaria

“…A particularly striking finding was the expression of variant antigen gene families across the infection phases. A total of 117 genes or gene fragments annotated in the genome as the schizont-infected cell agglutination variant antigen (SICAvar) genes (30,31) or SICAvar-like were differentially expressed across the phases, with one distinct cluster of SICAvar genes having high expression at the post-subRx and chronic phases and another showing high expression in the acute and post-subRx phases ( Figure 6B). In addition, 63 genes annotated as kir or vir (i.e., orthologous to the Plasmodium interspersed repeat (pir) families in other Plasmodium species [ref.…”

PacBio assembly of aPlasmodium knowlesigenome sequence with Hi-C correction and manual annotation of theSICAvargene family

“…Plasmodium knowlesi has served as a model parasite for malaria research for over 50 years, as detailed elsewhere in this special issue (Galinski et al 2017 ; Pasini et al 2017 ). Here we stress the importance and value of a well-assembled and annotated genome sequence for the continued benefit of many aspects of this research.…”

Comparative 3D genome organization in apicomplexan parasites

“…All Plasmodium species contain virulence genes that belong to the Plasmodium interspersed repeat (pir) superfamily. In addition, P. falciparum and P. knowlesi have evolved unique gene families that orchestrate these parasites to undergo antigenic variation, called var and SICAvar, respectively (7,8). During the process of antigenic variation, the parasite can escape from host immune responses by changing which members of these large families of parasite antigens are expressed.…”

“…Similar to the pir genes, most var genes are located in the subtelomeric regions of all 14 P. falciparum chromosomes, although several chromosomes also harbor internal var genes. The SICAvar genes are distributed more evenly along the chromosomes, with only a few located in subtelomeric regions (7). One of the mechanisms involved in the complex network of clonal var gene expression is localization of these genes in perinuclear clusters of heterochromatin (28,29).…”