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Attenuated Plasmodium yoelii lacking purine nucleoside phosphorylase confer protective immunity

Nature Medicine volume 14, pages 954–958 (2008)Cite this article

Abstract

Malaria continues to devastate sub-Saharan Africa owing to the emergence of drug resistance to established antimalarials and to the lack of an efficacious vaccine. Plasmodium species have a unique streamlined purine pathway in which the dual specificity enzyme purine nucleoside phosphorylase (PNP) functions in both purine recycling and purine salvage1,2,3,4. To evaluate the importance of PNP in an in vivo model of malaria, we disrupted PyPNP, the gene encoding PNP in the lethal Plasmodium yoelii YM strain. P. yoelii parasites lacking PNP were attenuated and cleared in mice. Although able to form gametocytes, PNP-deficient parasites did not form oocysts in mosquito midguts and were not transmitted from mosquitoes to mice. Mice given PNP-deficient parasites were immune to subsequent challenge to a lethal inoculum of P. yoelii YM and to challenge from P. yoelii 17XNL, another strain. These in vivo studies with PNP-deficient parasites support purine salvage as a target for antimalarials. They also suggest a strategy for the development of attenuated nontransmissible metabolic mutants as blood-stage malaria vaccine strains.

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Figure 1: P.yoelii lacking PNP are attenuated.

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Acknowledgements

This work was supported by US National Institutes of Health grant R21AI052469 and US Army Research Grant W81XWH-05-2-0025 (both to K.K.). P.S. and A.C. were supported by US National Institutes of Health grant R01 AI056840. We gratefully thank V. Schramm for review of the manuscript before submission, J. Nonon and S. Gonzalez for technical support during mosquito rearing and infection, V. Lagal for advice on PCR and A. Mwakingwe for assistance with sporozoite challenge experiments. We also thank V. Schramm for advice on biochemical assays and many stimulating discussions during the course of this work.

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Authors and Affiliations

  1. Departments of Medicine and Microbiology & Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    Li-Min Ting, Mathieu Gissot & Kami Kim

  2. Department of Medical Parasitology, New York University School of Medicine, 341 East 25th Street, New York, 10010, New York, USA

    Alida Coppi & Photini Sinnis

Authors
  1. Li-Min Ting
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  2. Mathieu Gissot
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  4. Photini Sinnis
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Contributions

L.-M.T., M.G. and A.C. performed experiments. L.-M.T., P.S. and K.K. planned experiments and analyzed data. L.-M.T. and K.K. wrote the manuscript.

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Correspondence to Kami Kim.

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Supplementary Figs. 1–4, Supplementary Table 1 and Supplementary Methods (PDF 452 kb)

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Ting, LM., Gissot, M., Coppi, A. et al. Attenuated Plasmodium yoelii lacking purine nucleoside phosphorylase confer protective immunity. Nat Med 14, 954–958 (2008). https://doi.org/10.1038/nm.1867

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