DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.

During blood stage infection, Plasmodium falciparum infected erythrocytes (IE) bind to host blood vessels. This virulence determinant enables parasites to evade spleen-dependent killing mechanisms, but paradoxically in some cases may reduce parasite fitness by killing the host. Adhesion of infected...

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Autores principales:	Marion Avril, Andrew J Brazier, Martin Melcher, Sowmya Sampath, Joseph D Smith
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/287b3d6669de49d2a81320fa18e38957
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spelling	oai:doaj.org-article:287b3d6669de49d2a81320fa18e389572021-11-18T06:05:28ZDC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.1553-73661553-737410.1371/journal.ppat.1003430https://doaj.org/article/287b3d6669de49d2a81320fa18e389572013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23825944/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374During blood stage infection, Plasmodium falciparum infected erythrocytes (IE) bind to host blood vessels. This virulence determinant enables parasites to evade spleen-dependent killing mechanisms, but paradoxically in some cases may reduce parasite fitness by killing the host. Adhesion of infected erythrocytes is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1), a family of polymorphic adhesion proteins encoded by var genes. Whereas cerebral binding and severe malaria are associated with parasites expressing DC8 and DC13 var genes, relatively little is known about the non-brain endothelial selection on severe malaria adhesive types. In this study, we selected P. falciparum-IEs on diverse endothelial cell types and demonstrate that DC8 and DC13 var genes were consistently among the major var transcripts selected on non-brain endothelial cells (lung, heart, bone marrow). To investigate the molecular basis for this avid endothelial binding activity, recombinant proteins were expressed from the predominant upregulated DC8 transcript, IT4var19. In-depth binding comparisons revealed that multiple extracellular domains from this protein bound brain and non-brain endothelial cells, and individual domains largely did not discriminate between different endothelial cell types. Additionally, we found that recombinant DC8 and DC13 CIDR1 domains exhibited a widespread endothelial binding activity and could compete for DC8-IE binding to brain endothelial cells, suggesting they may bind the same host receptor. Our findings provide new insights into the interaction of severe malaria adhesive types and host blood vessels and support the hypothesis that parasites causing severe malaria express PfEMP1 variants with a superior ability to adhere to diverse endothelial cell types, and may therefore endow these parasites with a growth and transmission advantage.Marion AvrilAndrew J BrazierMartin MelcherSowmya SampathJoseph D SmithPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 6, p e1003430 (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 Marion Avril Andrew J Brazier Martin Melcher Sowmya Sampath Joseph D Smith DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.
description	During blood stage infection, Plasmodium falciparum infected erythrocytes (IE) bind to host blood vessels. This virulence determinant enables parasites to evade spleen-dependent killing mechanisms, but paradoxically in some cases may reduce parasite fitness by killing the host. Adhesion of infected erythrocytes is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1), a family of polymorphic adhesion proteins encoded by var genes. Whereas cerebral binding and severe malaria are associated with parasites expressing DC8 and DC13 var genes, relatively little is known about the non-brain endothelial selection on severe malaria adhesive types. In this study, we selected P. falciparum-IEs on diverse endothelial cell types and demonstrate that DC8 and DC13 var genes were consistently among the major var transcripts selected on non-brain endothelial cells (lung, heart, bone marrow). To investigate the molecular basis for this avid endothelial binding activity, recombinant proteins were expressed from the predominant upregulated DC8 transcript, IT4var19. In-depth binding comparisons revealed that multiple extracellular domains from this protein bound brain and non-brain endothelial cells, and individual domains largely did not discriminate between different endothelial cell types. Additionally, we found that recombinant DC8 and DC13 CIDR1 domains exhibited a widespread endothelial binding activity and could compete for DC8-IE binding to brain endothelial cells, suggesting they may bind the same host receptor. Our findings provide new insights into the interaction of severe malaria adhesive types and host blood vessels and support the hypothesis that parasites causing severe malaria express PfEMP1 variants with a superior ability to adhere to diverse endothelial cell types, and may therefore endow these parasites with a growth and transmission advantage.
format	article
author	Marion Avril Andrew J Brazier Martin Melcher Sowmya Sampath Joseph D Smith
author_facet	Marion Avril Andrew J Brazier Martin Melcher Sowmya Sampath Joseph D Smith
author_sort	Marion Avril
title	DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.
title_short	DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.
title_full	DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.
title_fullStr	DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.
title_full_unstemmed	DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.
title_sort	dc8 and dc13 var genes associated with severe malaria bind avidly to diverse endothelial cells.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/287b3d6669de49d2a81320fa18e38957
work_keys_str_mv	AT marionavril dc8anddc13vargenesassociatedwithseveremalariabindavidlytodiverseendothelialcells AT andrewjbrazier dc8anddc13vargenesassociatedwithseveremalariabindavidlytodiverseendothelialcells AT martinmelcher dc8anddc13vargenesassociatedwithseveremalariabindavidlytodiverseendothelialcells AT sowmyasampath dc8anddc13vargenesassociatedwithseveremalariabindavidlytodiverseendothelialcells AT josephdsmith dc8anddc13vargenesassociatedwithseveremalariabindavidlytodiverseendothelialcells
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DC8 and DC13 var genes associated with severe malaria bind avidly to diverse endothelial cells.

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