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PARASITE BIOLOGY

Overcoming supply issues

Nature Reviews Microbiology volume 20, page 64 (2022)Cite this article

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During the blood stage of malaria development, parasites replicate within a membrane-bound parasitophorous vacuole (PV), which can access small molecules from the host through nutrient-permeable channels (NPCs) in the parasitophorous vacuolar membrane. Previous work suggests that upregulation of the parasite protein EXP1, which is required for NPC activity, is associated with artemisinin resistance (ARTR). ARTR is associated with fitness costs, and it was previously hypothesized that this could be due to a reduced haemoglobin-derived amino acid supply to parasites. In a recent study, Mesén-Ramírez et al. found that PV NPCs are conductive to major nutrients and act as gate for several antimalarials, and provide evidence that NPC upregulation increases the acquisition of amino acids by ARTR parasites to compensate for fitness costs.

Interestingly, the authors noticed that parasites with low EXP1 and NPC activities were hypersensitive to one antimalarial in particular (piperaquine; PPQ). Previous work suggests that PPQ inhibits haemoglobin proteolysis, thus limiting the supply of amino acids to parasites. Indeed, parasites treated with PPQ were hypersensitive to amino acid restriction, and overexpression of exp1 increased the growth of PPQ-treated parasites when amino acids were restricted, suggesting that increasing NPC activity restores the supply of amino acids from the host when haemoglobin proteolysis is blocked. Next, the authors found that a shortage in haemoglobin-derived amino acids causes a fitness cost in parasites with ARTR. Because NPC activity is crucial for amino acid acquisition, they hypothesized that enhancing the levels of EXP1 could compensate for the fitness cost by increasing the supply of amino acids to parasites with ARTR. Importantly, overexpression of exp1 in mutant Kelch13 parasites with ARTR reduced the growth defect under limiting amino acid conditions.

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References

Original article

  • Mesén-Ramírez, P. et al. The parasitophorous vacuole nutrient channel is critical for drug access in malaria parasites and modulates the artemisinin resistance fitness cost. Cell Host Microbe 29, 1774–1787 (2021)

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  1. Nature Reviews Microbiology http://www.nature.com/nrmicro/

    Ashley York

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  1. Ashley York
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Correspondence to Ashley York.

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York, A. Overcoming supply issues. Nat Rev Microbiol 20, 64 (2022). https://doi.org/10.1038/s41579-021-00676-8

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  • DOI: https://doi.org/10.1038/s41579-021-00676-8

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