Binding Heterogeneity of <named-content content-type="genus-species">Plasmodium falciparum</named-content> to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1

ABSTRACT Cerebral malaria is a severe neurological complication associated with sequestration of Plasmodium falciparum-infected erythrocytes (IE) in the brain microvasculature, but the specific binding interactions remain under debate. Here, we have generated an engineered three-dimensional (3D) hum...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Maria Bernabeu, Celina Gunnarsson, Maria Vishnyakova, Caitlin C. Howard, Ryan J. Nagao, Marion Avril, Terrie E. Taylor, Karl B. Seydel, Ying Zheng, Joseph D. Smith
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	PfEMP1 Plasmodium falciparum cerebral malaria microvessels tissue engineering Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e8baabff64bb490f8a669a8d2a19155f
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e8baabff64bb490f8a669a8d2a19155f
record_format	dspace
spelling	oai:doaj.org-article:e8baabff64bb490f8a669a8d2a19155f2021-11-15T15:55:24ZBinding Heterogeneity of <named-content content-type="genus-species">Plasmodium falciparum</named-content> to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-110.1128/mBio.00420-192150-7511https://doaj.org/article/e8baabff64bb490f8a669a8d2a19155f2019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00420-19https://doaj.org/toc/2150-7511ABSTRACT Cerebral malaria is a severe neurological complication associated with sequestration of Plasmodium falciparum-infected erythrocytes (IE) in the brain microvasculature, but the specific binding interactions remain under debate. Here, we have generated an engineered three-dimensional (3D) human brain endothelial microvessel model and studied P. falciparum binding under the large range of physiological flow velocities that occur in both health and disease. Perfusion assays on 3D microvessels reveal previously unappreciated phenotypic heterogeneity in parasite binding to tumor necrosis factor alpha (TNF-α)-activated brain endothelial cells. While clonal parasite lines expressing a group B P. falciparum erythrocyte membrane protein 1 (PfEMP1) present an increase in binding to activated 3D microvessels, P. falciparum-IE expressing DC8-PfEMP1 present a decrease in binding. The differential response to endothelium activation is mediated by surface expression changes of endothelial protein C receptor (EPCR) and intercellular adhesion molecule 1 (ICAM-1). These findings demonstrate heterogeneity in parasite binding and provide evidence for a parasite strategy to adapt to a changing microvascular environment during infection. The engineered 3D human brain microvessel model provides new mechanistic insight into parasite binding and opens opportunities for further studies on malaria pathogenesis and parasite-vessel interactions. IMPORTANCE Cerebral malaria research has been hindered by the inaccessibility of the brain. Here, we have developed an engineered 3D human brain microvessel model that mimics the blood flow rates and architecture of small blood vessels to study how P. falciparum-infected human erythrocytes attach to brain endothelial cells. By studying parasite lines with different adhesive properties, we show that the malaria parasite binding rate is heterogeneous and strongly influenced by physiological differences in flow and whether the endothelium has been previously activated by TNF-α, a proinflammatory cytokine that is linked to malaria disease severity. We also show the importance of human EPCR and ICAM-1 in parasite binding. Our model sheds new light on how P. falciparum binds within brain microvessels and provides a powerful method for future investigations of recruitment of human brain pathogens to the blood vessel lining of the brain.Maria BernabeuCelina GunnarssonMaria VishnyakovaCaitlin C. HowardRyan J. NagaoMarion AvrilTerrie E. TaylorKarl B. SeydelYing ZhengJoseph D. SmithAmerican Society for MicrobiologyarticlePfEMP1Plasmodium falciparumcerebral malariamicrovesselstissue engineeringMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	PfEMP1 Plasmodium falciparum cerebral malaria microvessels tissue engineering Microbiology QR1-502
spellingShingle	PfEMP1 Plasmodium falciparum cerebral malaria microvessels tissue engineering Microbiology QR1-502 Maria Bernabeu Celina Gunnarsson Maria Vishnyakova Caitlin C. Howard Ryan J. Nagao Marion Avril Terrie E. Taylor Karl B. Seydel Ying Zheng Joseph D. Smith Binding Heterogeneity of <named-content content-type="genus-species">Plasmodium falciparum</named-content> to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1
description	ABSTRACT Cerebral malaria is a severe neurological complication associated with sequestration of Plasmodium falciparum-infected erythrocytes (IE) in the brain microvasculature, but the specific binding interactions remain under debate. Here, we have generated an engineered three-dimensional (3D) human brain endothelial microvessel model and studied P. falciparum binding under the large range of physiological flow velocities that occur in both health and disease. Perfusion assays on 3D microvessels reveal previously unappreciated phenotypic heterogeneity in parasite binding to tumor necrosis factor alpha (TNF-α)-activated brain endothelial cells. While clonal parasite lines expressing a group B P. falciparum erythrocyte membrane protein 1 (PfEMP1) present an increase in binding to activated 3D microvessels, P. falciparum-IE expressing DC8-PfEMP1 present a decrease in binding. The differential response to endothelium activation is mediated by surface expression changes of endothelial protein C receptor (EPCR) and intercellular adhesion molecule 1 (ICAM-1). These findings demonstrate heterogeneity in parasite binding and provide evidence for a parasite strategy to adapt to a changing microvascular environment during infection. The engineered 3D human brain microvessel model provides new mechanistic insight into parasite binding and opens opportunities for further studies on malaria pathogenesis and parasite-vessel interactions. IMPORTANCE Cerebral malaria research has been hindered by the inaccessibility of the brain. Here, we have developed an engineered 3D human brain microvessel model that mimics the blood flow rates and architecture of small blood vessels to study how P. falciparum-infected human erythrocytes attach to brain endothelial cells. By studying parasite lines with different adhesive properties, we show that the malaria parasite binding rate is heterogeneous and strongly influenced by physiological differences in flow and whether the endothelium has been previously activated by TNF-α, a proinflammatory cytokine that is linked to malaria disease severity. We also show the importance of human EPCR and ICAM-1 in parasite binding. Our model sheds new light on how P. falciparum binds within brain microvessels and provides a powerful method for future investigations of recruitment of human brain pathogens to the blood vessel lining of the brain.
format	article
author	Maria Bernabeu Celina Gunnarsson Maria Vishnyakova Caitlin C. Howard Ryan J. Nagao Marion Avril Terrie E. Taylor Karl B. Seydel Ying Zheng Joseph D. Smith
author_facet	Maria Bernabeu Celina Gunnarsson Maria Vishnyakova Caitlin C. Howard Ryan J. Nagao Marion Avril Terrie E. Taylor Karl B. Seydel Ying Zheng Joseph D. Smith
author_sort	Maria Bernabeu
title	Binding Heterogeneity of <named-content content-type="genus-species">Plasmodium falciparum</named-content> to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1
title_short	Binding Heterogeneity of <named-content content-type="genus-species">Plasmodium falciparum</named-content> to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1
title_full	Binding Heterogeneity of <named-content content-type="genus-species">Plasmodium falciparum</named-content> to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1
title_fullStr	Binding Heterogeneity of <named-content content-type="genus-species">Plasmodium falciparum</named-content> to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1
title_full_unstemmed	Binding Heterogeneity of <named-content content-type="genus-species">Plasmodium falciparum</named-content> to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1
title_sort	binding heterogeneity of <named-content content-type="genus-species">plasmodium falciparum</named-content> to engineered 3d brain microvessels is mediated by epcr and icam-1
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/e8baabff64bb490f8a669a8d2a19155f
work_keys_str_mv	AT mariabernabeu bindingheterogeneityofnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontenttoengineered3dbrainmicrovesselsismediatedbyepcrandicam1 AT celinagunnarsson bindingheterogeneityofnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontenttoengineered3dbrainmicrovesselsismediatedbyepcrandicam1 AT mariavishnyakova bindingheterogeneityofnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontenttoengineered3dbrainmicrovesselsismediatedbyepcrandicam1 AT caitlinchoward bindingheterogeneityofnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontenttoengineered3dbrainmicrovesselsismediatedbyepcrandicam1 AT ryanjnagao bindingheterogeneityofnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontenttoengineered3dbrainmicrovesselsismediatedbyepcrandicam1 AT marionavril bindingheterogeneityofnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontenttoengineered3dbrainmicrovesselsismediatedbyepcrandicam1 AT terrieetaylor bindingheterogeneityofnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontenttoengineered3dbrainmicrovesselsismediatedbyepcrandicam1 AT karlbseydel bindingheterogeneityofnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontenttoengineered3dbrainmicrovesselsismediatedbyepcrandicam1 AT yingzheng bindingheterogeneityofnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontenttoengineered3dbrainmicrovesselsismediatedbyepcrandicam1 AT josephdsmith bindingheterogeneityofnamedcontentcontenttypegenusspeciesplasmodiumfalciparumnamedcontenttoengineered3dbrainmicrovesselsismediatedbyepcrandicam1
_version_	1718427186850955264

Binding Heterogeneity of <named-content content-type="genus-species">Plasmodium falciparum</named-content> to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1

Ejemplares similares