• Document: Differential activity of methylene blue against erythrocytic and hepatic stages of Plasmodium
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Malaria Journal Bosson‑Vanga et al. Malar J (2018) 17:143 https://doi.org/10.1186/s12936-018-2300-y RESEARCH Open Access Differential activity of methylene blue against erythrocytic and hepatic stages of Plasmodium Henriette Bosson‑Vanga1,2*  , Jean‑François Franetich1, Valérie Soulard1, Daniel Sossau1,3, Maurel Tefit1, Bocar Kane4, Jean‑Christophe Vaillant5, Steffen Borrmann6,7, Olaf Müller8, Nathalie Dereuddre‑Bosquet9, Roger Le Grand9, Olivier Silvie1 and Dominique Mazier1,10* Abstract  Background:  In the context of malaria elimination/eradication, drugs that are effective against the different develop‑ mental stages of the parasite are highly desirable. The oldest synthetic anti-malarial drug, the thiazine dye methylene blue (MB), is known for its activity against Plasmodium blood stages, including gametocytes. The aim of the present study was to investigate a possible effect of MB against malaria parasite liver stages. Methods:  MB activity was investigated using both in vitro and in vivo models. In vitro assays consisted of testing MB activity on Plasmodium falciparum, Plasmodium cynomolgi and Plasmodium yoelii parasites in human, simian or murine primary hepatocytes, respectively. MB in vivo activity was evaluated using intravital imaging in BALB/c mice infected with a transgenic bioluminescent P. yoelii parasite line. The transmission-blocking activity of MB was also addressed using mosquitoes fed on MB-treated mice. Results:  MB shows no activity on Plasmodium liver stages, including hypnozoites, in vitro in primary hepatocytes. In BALB/c mice, MB has moderate effect on P. yoelii hepatic development but is highly effective against blood stage growth. MB is active against gametocytes and abrogates parasite transmission from mice to mosquitoes. Conclusion:  While confirming activity of MB against both sexual and asexual blood stages, the results indicate that MB has only little activity on the development of the hepatic stages of malaria parasites. Keywords:  Malaria, Methylene blue (MB), Exoerythrocytic stages, Plasmodium, Blocking malaria transmission Background Human malaria is caused by five different species of Malaria remains a major cause of morbidity and mortal- Plasmodium parasites. Plasmodium falciparum and ity in many regions of the world [1]. In 2016 the World Plasmodium vivax are the most common forms with Health Organization estimated a total of 212 million P. falciparum being the deadliest. Due to the ability to cases of malaria, which resulted in 429,000 deaths. Afri- rapidly develop drug resistance, Plasmodium parasites can populations, particularly children younger than continue to be a major challenge for effective case man- 5  years old, are the most affected by this disease [2]. agement [3, 4]. Malaria parasites consist of several life cycle stages that have to be individually targeted to reach malaria elimination [5]. *Correspondence: bossonhenriette@gmail.com; dominique. Most of the drugs used for the treatment of malaria mazier@upmc.fr 1 Sorbonne Université, Inserm, CNRS, Centre d’Immunologie et des act as erythrocytic stage inhibitors. The ambitious goal Maladies Infectieuses, U1135, ERL8255, CIMI-Paris, F‑75013 PARIS, France of malaria elimination, however, requires strategies to 10 Service de Parasitologie‑Mycologie, Centre National de Référence du prevent parasite transmission between the human host Paludisme, AP-HP, Groupe Hospitalier Pitié Salpêtrière, 83 Bd de l’hôpital, 75013 PARIS, France and the mosquito vector, thus targeting the hepatic Full list of author information is available at the end of the article or the gametocyte developmental stages [6]. To date, © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medi

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