Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors
Kayode K. Ojo, … , Oliver Billker, Wesley C. Van Voorhis
Kayode K. Ojo, … , Oliver Billker, Wesley C. Van Voorhis
Published May 8, 2012
Citation Information: J Clin Invest. 2012;122(6):2301-2305. https://doi.org/10.1172/JCI61822.
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Brief Report Infectious disease

Transmission of malaria to mosquitoes blocked by bumped kinase inhibitors

Abstract

Effective control and eradication of malaria will require new tools to prevent transmission. Current antimalarial therapies targeting the asexual stage of Plasmodium do not prevent transmission of circulating gametocytes from infected humans to mosquitoes. Here, we describe a new class of transmission-blocking compounds, bumped kinase inhibitors (BKIs), which inhibit microgametocyte exflagellation. Oocyst formation and sporozoite production, necessary for transmission to mammals, were inhibited in mosquitoes fed on either BKI-1–treated human blood or mice treated with BKI-1. BKIs are hypothesized to act via inhibition of Plasmodium calcium-dependent protein kinase 4 and predicted to have little activity against mammalian kinases. Our data show that BKIs do not inhibit proliferation of mammalian cell lines and are well tolerated in mice. Used in combination with drugs active against asexual stages of Plasmodium, BKIs could prove an important tool for malaria control and eradication.

Authors

Kayode K. Ojo, Claudia Pfander, Natascha R. Mueller, Charlotte Burstroem, Eric T. Larson, Cassie M. Bryan, Anna M.W. Fox, Molly C. Reid, Steven M. Johnson, Ryan C. Murphy, Mark Kennedy, Henning Mann, David J. Leibly, Stephen N. Hewitt, Christophe L.M.J. Verlinde, Stefan Kappe, Ethan A. Merritt, Dustin J. Maly, Oliver Billker, Wesley C. Van Voorhis

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Figure 3

BKI-1 blocks formation of oocysts and thus malaria infection of mosquitoes.

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BKI-1 blocks formation of oocysts and thus malaria infection of mosquito...
(A) Mice were infected with GFP-expressing P. berghei and treated with compounds at 3 mg/kg or 10 mg/kg i.p., and 30 minutes later, mosquitoes were fed on mice. Shown are the geometric mean oocyst number on 8–20 dissected mosquito midguts explanted 5 days after feeding. Fluorescence micrographs illustrate typical infection levels in mosquitoes fed on control and BKI-1–treated mice. Scale bar: 500 μm. Data are representative of 3 experiments. Error bars represent SEM. (B) Compounds were mixed with human blood and aliquots explanted for exflagellation observation, and the blood was fed to A. stephensi mosquitoes. A complete suppression of exflagellation was observed with 1 and 3 μM BKI-1. Blocking exflagellation with BKI-1 correlated well with the prevention of oocyst and infective sporozoite formation. Sexual stage development in mosquitoes fed with 0.1 μM was not completely but was significantly reduced, as shown by more than 86% in the number of oocyst and infective sporozoites. In a repeat experiment, exflagellation events in the presence of BKI-1 were suppressed completely at 1 or 3 μM and more than 90% at 0.3 μM.