Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.

Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but als...

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Autores principales:	Steve M Taylor, Carla Cerami, Rick M Fairhurst
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/b786a980c330434f89ac4eb3d25c10a7
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spelling	oai:doaj.org-article:b786a980c330434f89ac4eb3d25c10a72021-11-18T06:05:39ZHemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.1553-73661553-737410.1371/journal.ppat.1003327https://doaj.org/article/b786a980c330434f89ac4eb3d25c10a72013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23696730/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but also cause hemoglobinopathies. These genetic traits--including hemoglobin S (HbS), hemoglobin C (HbC), and α-thalassemia--are the most common monogenic human disorders and can confer remarkable degrees of protection from severe, life-threatening falciparum malaria in African children: the risk is reduced 70% by homozygous HbC and 90% by heterozygous HbS (sickle-cell trait). Importantly, this protection is principally present for severe disease and largely absent for P. falciparum infection, suggesting that these hemoglobinopathies specifically neutralize the parasite's in vivo mechanisms of pathogenesis. These hemoglobin variants thus represent a "natural experiment" to identify the cellular and molecular mechanisms by which P. falciparum produces clinical morbidity, which remain partially obscured due to the complexity of interactions between this parasite and its human host. Multiple lines of evidence support a restriction of parasite growth by various hemoglobinopathies, and recent data suggest this phenomenon may result from host microRNA interference with parasite metabolism. Multiple hemoglobinopathies mitigate the pathogenic potential of parasites by interfering with the export of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of the host red blood cell. Few studies have investigated their effects upon the activation of the innate and adaptive immune systems, although recent murine studies suggest a role for heme oxygenase-1 in protection. Ultimately, the identification of mechanisms of protection and pathogenesis can inform future therapeutics and preventive measures. Hemoglobinopathies slice the "Gordian knot" of host and parasite interactions to confer malaria protection, and offer a translational model to identify the most critical mechanisms of P. falciparum pathogenesis.Steve M TaylorCarla CeramiRick M FairhurstPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 5, p e1003327 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Steve M Taylor Carla Cerami Rick M Fairhurst Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.
description	Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but also cause hemoglobinopathies. These genetic traits--including hemoglobin S (HbS), hemoglobin C (HbC), and α-thalassemia--are the most common monogenic human disorders and can confer remarkable degrees of protection from severe, life-threatening falciparum malaria in African children: the risk is reduced 70% by homozygous HbC and 90% by heterozygous HbS (sickle-cell trait). Importantly, this protection is principally present for severe disease and largely absent for P. falciparum infection, suggesting that these hemoglobinopathies specifically neutralize the parasite's in vivo mechanisms of pathogenesis. These hemoglobin variants thus represent a "natural experiment" to identify the cellular and molecular mechanisms by which P. falciparum produces clinical morbidity, which remain partially obscured due to the complexity of interactions between this parasite and its human host. Multiple lines of evidence support a restriction of parasite growth by various hemoglobinopathies, and recent data suggest this phenomenon may result from host microRNA interference with parasite metabolism. Multiple hemoglobinopathies mitigate the pathogenic potential of parasites by interfering with the export of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of the host red blood cell. Few studies have investigated their effects upon the activation of the innate and adaptive immune systems, although recent murine studies suggest a role for heme oxygenase-1 in protection. Ultimately, the identification of mechanisms of protection and pathogenesis can inform future therapeutics and preventive measures. Hemoglobinopathies slice the "Gordian knot" of host and parasite interactions to confer malaria protection, and offer a translational model to identify the most critical mechanisms of P. falciparum pathogenesis.
format	article
author	Steve M Taylor Carla Cerami Rick M Fairhurst
author_facet	Steve M Taylor Carla Cerami Rick M Fairhurst
author_sort	Steve M Taylor
title	Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.
title_short	Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.
title_full	Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.
title_fullStr	Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.
title_full_unstemmed	Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.
title_sort	hemoglobinopathies: slicing the gordian knot of plasmodium falciparum malaria pathogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/b786a980c330434f89ac4eb3d25c10a7
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Hemoglobinopathies: slicing the Gordian knot of Plasmodium falciparum malaria pathogenesis.

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