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Can we stop malaria parasites in the skin?

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Background

Since the discovery of malaria transmission by mosquitoes, it was assumed that the parasites are injected directly into the blood stream. However, indirect experiments [1] and direct microscopic observations using mice as hosts and fluorescent rodent malaria species showed that the parasites are instead injected into the skin. These Plasmodium sporozoites then migrate rapidly through the dermis and enter blood or lymph vessels [2]. Stopping sporozoite motility also halts infection [3]. We aim at understanding the mechanisms that drive sporozoite motility and identify drug-like compounds that stop parasite locomotion. To this end, we have adapted and developed new methods including a screening pipeline to test small molecules that could interfere with motility and thus stop Plasmodium transmission at the skin stage [4, 5].

Materials and methods

A screening pipeline was developed that allowed medium-throughput assessment of small molecules as possible inhibitors of sporozoite motility in vitro. This was followed by in vivo testing during transmission from mosquito to mouse.

Results

We tested over 200 compounds selected from a library of drugs approved by the Federal Drug Administration for their potential to interfere with motility. We identified two molecules that inhibited in vitro motility in the nano-molar range. When these two compounds were tested during the transmission by mosquitoes, an ectopically applied drug resulted in a decrease of transmission efficiency while an orally given drug showed no effect on transmission at non-toxic doses.

References

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    Sidjanski SP, Vanderberg JP: Delayed migration of Plasmodium sporozoites from the mosquito bite site to the blood. Am J Trop Med Hyg. 1997, 57: 426-429.

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    Amino R, Thiberge S, Martin B, Celli S, Shorte S, Frischknecht F, Ménard R: Quantitative imaging of Plasmodium transmission from mosquito to mammal. Nat Med. 2006, 12: 220-224. 10.1038/nm1350.

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    Kebaier C, Voza T, Vanderberg J: Kinetics of mosquito-injected Plasmodium sporozoites in mice: fewer sporozoites are injected into sporozoite-immunized mice. PLoS Pathog. 2009, 5: e1000399-10.1371/journal.ppat.1000399.

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    Hegge S, Kudryashev M, Smith A, Frischknecht F: Automated classification of Plasmodium sporozoite movement patterns reveals a shift towards productive motility during salivary gland infection. Biotechnol J. 2009, 4: 903-913. 10.1002/biot.200900007.

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    Hegge S, Münter S, Steinbüchel M, Heiss K, Engel U, Matuschewski K, Frischknecht F: Multistep adhesion of Plasmodium sporozoites. FASEB J. 2010, 24: 2222-2234. 10.1096/fj.09-148700.

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Author information

Correspondence to Friedrich Frischknecht.

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Cite this article

Douglas, R., Ester, M., Hellmann, J. et al. Can we stop malaria parasites in the skin?. Malar J 13, O7 (2014) doi:10.1186/1475-2875-13-S1-O7

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Keywords

  • Malaria
  • Small Molecule
  • Plasmodium
  • Microscopic Observation
  • Lymph Vessel

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