Human red blood cell-adapted Plasmodium knowlesi parasites: a new model system for malaria research

Abstract

Plasmodium knowlesi is a simian malaria parasite primarily infecting macaque species in Southeast Asia. Although its capacity to infect humans has been recognized since the early part of the last century, it has recently become evident that human infections are widespread and potentially life threatening. Historically, P. knowlesi has proven to be a powerful tool in early studies of malaria parasites, providing key breakthroughs in understanding many aspects of Plasmodium biology. However, the necessity to grow the parasite either in macaques or in vitro using macaque blood restricted research to laboratories with access to these resources. The recent adaptation of P. knowlesi to grow and proliferate in vitro in human red blood cells (RBCs) is therefore a substantial step towards revitalizing and expanding research on P. knowlesi. Furthermore, the development of a highly efficient transfection system to genetically modify the parasite makes P. knowlesi an ideal model to study parasite biology. In this review, we elaborate on the importance of P. knowlesi in earlier phases of malaria research and highlight the future potential of the newly available human adapted P. knowlesi parasite lines.

Figure 1. Adaptation procedure and switch in host cell preference of P. knowlesi

A. Comparison of P. falciparum and P. knowlesi schizonts and merozoites. P. knowlesi has fewer but larger merozoites in a mature schizont than P. falciparum. B. Schematic representation of the process used to adapt macaque restricted P. knowlesi parasites to in vitro growth in human RBCs. Macaque RBCs are depicted in dark-red and human RBCs in red. Scale bar represents 2μm. C. Switch in host cell preference to adapt to growth in RBCs. Graph shows the restriction of P. knowlesi grown in macaque blood to very young human RBCs and the subsequent expansion during adaptation to human blood towards a wider range of host cells. The subtle preference of P. falciparum for younger cells is also shown as reference.

Figure 2. Outline of new tools to advance malaria research using human red blood cell adapted P. knowlesi

The 24h P. knowlesi life cycle is depicted, starting with the invasion of a merozoite and subsequent development from ring to schizont stage. A selection of tools that can be applied to the human adapted P. knowlesi line is shown. The generation of a gametocyte-producing-line and transmission competent mosquito colonies would allow the research to expand to other life stages.