Arginine kills gametocytes

Plasmodium falciparum is able to sequester from peripheral circulation during infection. The asexual stage parasites sequester by binding to endothelial cell receptors in the microvasculature of various organs. Gametocytes also spend the almost ten days necessary for their maturation sequestered away from the peripheral circulation before they are released in blood mainstream. In contrast to those of asexual parasites, the mechanisms and cellular interactions responsible for immature gametocyte sequestration are largely unexplored, and controversial evidence has been produced so far on this matter. Cell adhesion of asexual stage parasites is consistently more efficient than that, virtually undetectable of immature gametocytes, irrespectively of the endothelial cell lines used and of parasite genotypes. Francesco Silvestrini, Marta Tibúrcio, Lucia Bertuccini, Pietro Alano. Differential Adhesive Properties of Sequestered Asexual and Sexual Stages of Plasmodium falciparum on Human Endothelial Cells Are Tissue Independent. PLOS , 2012 http://dx.doi.org/10.1371/journal.pone.0031567 A study of the Walter Reed Army Institute already in 1992 found that the herbicide Trifluralin showed strong anti-malarial effects not only on Plasmodium falciparum in cultures, but also transmission blocking by inhibiting gametocyte maturation and viability. Nath, Jayasree; Okoye, Vincent ; Schneider, Imogene. Anti-Malarial Effects of the Anti-Tubulin Herbicide Trifluralin: Studies with Plasmodium falciparum. Walter Reed Army Institue of Research Washington. PDF Url : ADA286439 Thiostrepton treatment of infected mice reduces transmission of parasites by more than ten-fold, indicating that the plastid has a role in sexual development of the parasite. These results also indicate that the plastid function of the apicoplast is accessible to drug action in vivo and important to the development of both sexual and asexual forms of the parasite. Makoah N. Aminake, Sebastian Schoof, Ludmilla Sologub, Monika Leubner, Marc Kirschner, Hans-Dieter Arndt, and Gabriele Pradel. Thiostrepton and Derivatives Exhibit Antimalarial and Gametocytocidal Activity by Dually Targeting Parasite Proteasome and Apicoplast. Antimicrob. Agents Chemother. April 2011; 55:4 1338-1348 Supply of the isoprenoid building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) is the essential metabolic function of the apicoplast for isoprenoid biosynthesis, particularly during gametocytogenesis. When IPP supplementation was removed early in gametocytogenesis, developmental defects were observed, supporting the essential role of isoprenoids for normal gametocytogenesis. Furthermore, mosquitoes infected with gametocytes lacking the apicoplast developed fewer and smaller oocysts that failed to produce sporozoites. This finding further supports the essential role of the apicoplast in establishing a successful infection in the mosquito vector. Jessica D. Wiley, Emilio F. Merino, Priscilla M. Krai, Kyle J. McLean, Abhai K. Tripathi, Joel Vega-Rodríguez, Marcelo Jacobs-Loren, Michael Klemba and Maria B. Cassera. Isoprenoid Precursor Biosynthesis Is the Essential Metabolic Role of the Apicoplast during Gametocytogenesis in Plasmodium falciparum. Eukaryotic Amino-acids in Artemisia plants have barely been studied. The analytical data published by EA Brisibe and J Ferreira date back to 2009 E Brisibe, Umoren , F Brisibe d, P Magalhäes, Jorge F.S. Ferreira , Nutritional characterisation and antioxidant capacity of different tissues of Artemisia annua L.Food Chemistry, 2009, 115, 1240-1246 Their role in malaria infections has been ignored, except for a study published in Japan. Uyen DT, Huy NT, Trang DT, Nhien NT, Oida T, Hirayama K, Harada S, Kamei K. Effects of amino acids on malarial heme crystallization. Biol Pharm Bull. 2008 Aug;31(8):1483-8. To gain insight into the mechanism of malarial haemozoin formation, they examined the effects of amino acids on beta hematin formation in vitro. Surprisingly some of these amino acids like arginine, histidine, lysine showed a significant inhibition. In contrast beta-hematin formation was enhanced by leucine, isoleucine, valine and methionine. A very recent paper from China Li Zheng, Yanyan Pan, Yonghui Feng, Liwang Cui and Yaming Cao. L-Arginine supplementation in mice enhances NO production in spleen cells and inhibits Plasmodium yoelii transmission in mosquitoes Parasites & Vectors 20158:326 DOI: 10.1186/s13071-015-0940-0 shows that arginine supplementation not only reduced parasitemia and prolonged survival of malaria infected mice by raising the NO produced endogenously, but also reduced the numbers of zygotes and oocysts in mosquitoes fed on infected blood containing arginine. This confirms earlier results from China. Nitric oxide inhibits the development of Plasmodium yoelii gametocytes into gametes Cao Ya-Ming, Tsuboi Torii, Development of Plasmodium yoelii gametocytes into gametes. Parasitology International 1998, 47, 157–166. Mellouk S, Green S, Nacy CA, Hoffman SL, IFN-gamma inhibits development of Plasmodium berghei exoerythrocytic stages in hepatocytes by an L-arginine-dependent effector mechanism. J Immunol. 1991 Jun 1;146(11):3971-6.. It inhibits the exflagellation of male gametocytes. Liu YJ, Wang JC, Feng H, Zhu XT, An CL, Cao YM. In vitro observation on effect of nitric oxide on exflagellation of Plasmodium yoelii. [Article in Chinese] Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 2007 Jun;25(3):206-8, 212 In the fight against malaria most efforts have concentrated on the elimination of asexual parasites and the symptoms they cause : fever, nausea, inflammation, coma…. The fight against the sexual forms, i.e. gametocytes has been neglected. It has occasionnally been observed that certain drugs like primaquine have a gametocydal effect. But primaquine is very toxic for people with the G6DP deficiency. Chloroquine and artemisinine only affect young gametocytes but have no effect on mature gametocytes. Sulfadoxine-pyrimethamine even increases the number of gametocytes. Anyway these pharmaceutical drugs are only administered during three days, and mature gametocytes develop on day ~14 of the infection. But arginine not only has an effect on gametocytes, but also on sporozoites and intrahepatic development of parasites. Activation of the nitric oxide pathway in the hepatocyte was found to be responsible for hepatocyte refractory status. A Nüssler, JC Drapier, L Rénia, S Pied, D Mazier. L-arginine-dependant destruction of intrahepatic maalaria parasites in response to TNF and IL6 stimulation. Eur J Immunol, 1991, 21, 227,-30 Nüssler AK, Rénia L, Mazier D. In vivo induction ot the no nitric oxide pathway in hepatocytes. Eur J Immunol, 1993, 23, 882-7 Protection against pre-erythrocytic stages of malaria is possible, as demonstrated by the resistance obtained by immunizing with irradiated sporozoites. This is the basis of the development of many antimalarial vaccines. However the involved mechanisms are more numerous and intricate than initially believed and this explains the failure of so many new vaccines in clincal trials. One fact however seems clear. Irradiated sporozoites activate the nitric oxide partway. But the killing effect of the NO produced in this way can easily interrupted by the injection of NOS inhibitors like NMA (NG-monomethyl. L-arginine). NO and reactive nitrogen species were found in intraerythrocytic Plasmodium falciparum parasites and their food vacuoles. D Mazier, L Regia, S Pied, M Kombila, Hepatic stages of malaria specific and non-specific factors inhibiting the developement. Parasitologia, 1993, 35, 59-63. The prophylactic properties of regular drinking of Artemisia tea have been noticed in many countries and documented in Uganda Ogwang PE, Ogwal JO, Kasasa S, Olila D, Ejobi F, Kabasa D, Obua C (2012) Artemisia annua L. infusion consumed once a week reduces risk of multiple episodes of malaria: a randomised trial in a Ugandan community. Trop J Pharmaceu Res 13:445-453. Maybe the same practice will reduce the gametocyte load in asymptomatic individuals and block transmisssion. That is what we want to find out in clinical trials with African partners.