Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria

ABSTRACT Malaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pa...

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Autores principales:	Emile B. Gordon, Geoffrey T. Hart, Tuan M. Tran, Michael Waisberg, Munir Akkaya, Jeff Skinner, Severin Zinöcker, Mirna Pena, Takele Yazew, Chen-Feng Qi, Louis H. Miller, Susan K. Pierce
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d9d29f731e7d438284e52153462fb045
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spelling	oai:doaj.org-article:d9d29f731e7d438284e52153462fb0452021-11-15T15:49:02ZInhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria10.1128/mBio.00725-152150-7511https://doaj.org/article/d9d29f731e7d438284e52153462fb0452015-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00725-15https://doaj.org/toc/2150-7511ABSTRACT Malaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4+ and CD8+ T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism. IMPORTANCE Malaria is a highly prevalent infectious disease caused by parasites of several Plasmodium spp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications of Plasmodium falciparum infection is cerebral malaria with a fatality rate of 15 to 20%, despite treatment with antimalarial drugs. Cerebral malaria takes a second toll on African children, leaving survivors at high risk of debilitating neurological defects. At present, we have no effective adjunctive therapies for cerebral malaria, and developing such therapies would have a large impact on saving young lives in Africa. Here we report results that open a new avenue for the development of highly selective adjunctive therapies for cerebral malaria by targeting pathways that regulate host and parasite metabolism.Emile B. GordonGeoffrey T. HartTuan M. TranMichael WaisbergMunir AkkayaJeff SkinnerSeverin ZinöckerMirna PenaTakele YazewChen-Feng QiLouis H. MillerSusan K. PierceAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 3 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Emile B. Gordon Geoffrey T. Hart Tuan M. Tran Michael Waisberg Munir Akkaya Jeff Skinner Severin Zinöcker Mirna Pena Takele Yazew Chen-Feng Qi Louis H. Miller Susan K. Pierce Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria
description	ABSTRACT Malaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4+ and CD8+ T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism. IMPORTANCE Malaria is a highly prevalent infectious disease caused by parasites of several Plasmodium spp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications of Plasmodium falciparum infection is cerebral malaria with a fatality rate of 15 to 20%, despite treatment with antimalarial drugs. Cerebral malaria takes a second toll on African children, leaving survivors at high risk of debilitating neurological defects. At present, we have no effective adjunctive therapies for cerebral malaria, and developing such therapies would have a large impact on saving young lives in Africa. Here we report results that open a new avenue for the development of highly selective adjunctive therapies for cerebral malaria by targeting pathways that regulate host and parasite metabolism.
format	article
author	Emile B. Gordon Geoffrey T. Hart Tuan M. Tran Michael Waisberg Munir Akkaya Jeff Skinner Severin Zinöcker Mirna Pena Takele Yazew Chen-Feng Qi Louis H. Miller Susan K. Pierce
author_facet	Emile B. Gordon Geoffrey T. Hart Tuan M. Tran Michael Waisberg Munir Akkaya Jeff Skinner Severin Zinöcker Mirna Pena Takele Yazew Chen-Feng Qi Louis H. Miller Susan K. Pierce
author_sort	Emile B. Gordon
title	Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria
title_short	Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria
title_full	Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria
title_fullStr	Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria
title_full_unstemmed	Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria
title_sort	inhibiting the mammalian target of rapamycin blocks the development of experimental cerebral malaria
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/d9d29f731e7d438284e52153462fb045
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Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria

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