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Adaptation of Plasmodium falciparum to its transmission environment

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Abstract

Success in eliminating malaria will depend on whether parasite evolution outpaces control efforts. Here, we show that Plasmodium falciparum parasites (the deadliest of the species causing human malaria) found in low-transmission-intensity areas have evolved to invest more in transmission to new hosts (reproduction) and less in within-host replication (growth) than parasites found in high-transmission areas. At the cellular level, this adaptation manifests as increased production of reproductive forms (gametocytes) early in the infection at the expense of processes associated with multiplication inside red blood cells, especially membrane transport and protein trafficking. At the molecular level, this manifests as changes in the expression levels of genes encoding epigenetic and translational machinery. Specifically, expression levels of the gene encoding AP2-G—the transcription factor that initiates reproduction—increase as transmission intensity decreases. This is accompanied by downregulation and upregulation of genes encoding HDAC1 and HDA1—two histone deacetylases that epigenetically regulate the parasite’s replicative and reproductive life-stage programmes, respectively. Parasites in reproductive mode show increased reliance on the prokaryotic translation machinery found inside the plastid-derived organelles. Thus, our dissection of the parasite’s adaptive regulatory architecture has identified new potential molecular targets for malaria control.

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Fig. 1: Experimental design and analysis.
Fig. 2: Full-genome gene correlation network.
Fig. 3: Epigenetic and translation machinery networks.
Fig. 4: Enrichment of organellar translation genes in downregulated H–L genes and sexual-stage network modules.
Fig. 5: Selection for environment-specific levels of replication and reproduction under two different trade-off models.

Change history

  • 26 August 2020

    In the HTML version of the article, the hyperlink for Supplementary Data 4 incorrectly directed to Supplementary Data 6. The PDF version was unaffected. This has now been corrected.

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Acknowledgements

This paper is published with the permission of the director of the Kenya Medical Research Institute (KEMRI). The authors are grateful to the study participants and the parasite culture laboratory at the KEMRI–Wellcome Trust Research Programme, Kilifi, Kenya. We also thank G. McFadden, M. Greischar and A. Read for helpful comments and H. Ginsburg for assistance with the gene sets for the enrichment tests. This work was supported by the Wellcome Trust (grant numbers 088634 to M.J.M. and 092741 and 077176 to K.M.).

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M.K.R., M.A.N., J.J.S., J.M.N., M.M.E., A.S.A., M.M.K. and M.J.M. collected the data. Z.B. and S.M. provided the microarray materials. I.M.E., J.N.W., K.M. and M.J.M. organized the field work. M.J.M. and M.K.R. prepared the manuscript.

Corresponding author

Correspondence to Margaret J. Mackinnon.

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The authors declare no competing financial interests.

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Supplementary information

Supplementary Information

Supplementary Figures 1–9; Supplementary Tables 1, 3 and 5; Legends for Supplementary Figures 10–11 and Supplementary Tables 2, 4, 6, 7 and 8; Supplementary references.

Life Sciences Reporting Summary

Supplementary Table 2

Genes showing significant differences in expression level between high (H) and low (L) transmission populations.

Supplementary Table 4

Summary of methods for adjusting for host, parasite and gene properties in the analyses.

Supplementary Table 6

Summary of network module properties.

Supplementary Table 7

Gene sets used for functional.

Supplementary Table 8

Abbreviated names for epigenetic and translational machinery genes used in the analyses.

Supplementary Figure 10

H–L differentiation among transport genes.

Supplementary Figure 11

H–L differentiation among trafficking genes.

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Rono, M.K., Nyonda, M.A., Simam, J.J. et al. Adaptation of Plasmodium falciparum to its transmission environment. Nat Ecol Evol 2, 377–387 (2018). https://doi.org/10.1038/s41559-017-0419-9

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