Plasmodium falciparum  erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood–brain barrier in cerebral malaria

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Plasmodium falciparum parasites causing cerebral malaria express specific PfEMP1 proteins (group A ^+CM) on infected erythrocytes. Group A ^+CM PfEMP1s allow entry into brain microvascular endothelial cells; this causes cell swelling and drives cerebral malaria pathology by disrupting the blood–brain barrier.

Abstract

Cerebral malaria (CM) is caused by the binding of Plasmodium falciparum–infected erythrocytes (IEs) to the brain microvasculature, leading to inflammation, vessel occlusion, and cerebral swelling. We have previously linked dual intercellular adhesion molecule-1 (ICAM-1)– and endothelial protein C receptor (EPCR)–binding P. falciparum parasites to these symptoms, but the mechanism driving the pathogenesis has not been identified. Here, we used a 3D spheroid model of the blood–brain barrier (BBB) to determine unexpected new features of IEs expressing the dual-receptor binding PfEMP1 parasite proteins. Analysis of multiple parasite lines shows that IEs are taken up by brain endothelial cells in an ICAM-1–dependent manner, resulting in breakdown of the BBB and swelling of the endothelial cells. Via ex vivo analysis of postmortem tissue samples from CM patients, we confirmed the presence of parasites within brain endothelial cells. Importantly, this discovery points to parasite ingress into the brain endothelium as a contributing factor to the pathology of human CM.

Graphical Abstract

Related collections

Most cited references 59

Record: found
Abstract: found
Article: not found

Fiji: an open-source platform for biological-image analysis.

Johannes Schindelin, Ignacio Arganda-Carreras, Erwin Frise … (2019)

Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.

0 comments Cited 13692 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Tissue Plasminogen Activator for Acute Ischemic Stroke

(1996)

Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials. We performed a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke. The trial had two parts. Part 1 (in which 291 patients were enrolled) tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS: In part 1, there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours, although a benefit was observed for the t-PA group at three months for all four outcome measures. In part 2, the long-term clinical benefit of t-PA predicted by the results of part 1 was confirmed (global odds ratio for a favorable outcome, 1.7; 95 percent confidence interval, 1.2 to 2.6). As compared with patients given placebo, patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales. Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t-PA but only 0.6 percent of patients given placebo (P < 0.001). Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group (P = 0.30). Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.

0 comments Cited 642 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Genome sequence of the human malaria parasite Plasmodium falciparum.

Malcolm J. Gardner, Neil Hall, Eula Fung … (2002)

The parasite Plasmodium falciparum is responsible for hundreds of millions of cases of malaria, and kills more than one million African children annually. Here we report an analysis of the genome sequence of P. falciparum clone 3D7. The 23-megabase nuclear genome consists of 14 chromosomes, encodes about 5,300 genes, and is the most (A + T)-rich genome sequenced to date. Genes involved in antigenic variation are concentrated in the subtelomeric regions of the chromosomes. Compared to the genomes of free-living eukaryotic microbes, the genome of this intracellular parasite encodes fewer enzymes and transporters, but a large proportion of genes are devoted to immune evasion and host-parasite interactions. Many nuclear-encoded proteins are targeted to the apicoplast, an organelle involved in fatty-acid and isoprenoid metabolism. The genome sequence provides the foundation for future studies of this organism, and is being exploited in the search for new drugs and vaccines to fight malaria.

0 comments Cited 296 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Yvonne Adams:

ORCID: https://orcid.org/0000-0001-8041-6580

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Rebecca W. Olsen:

ORCID: https://orcid.org/0000-0003-4034-4302

Role: InvestigationRole: Writing - review & editing

Anja Bengtsson:

ORCID: https://orcid.org/0000-0001-9523-8369

Role: Data curationRole: InvestigationRole: Methodology

Nanna Dalgaard:

ORCID: https://orcid.org/0000-0002-2584-9639

Role: Formal analysisRole: Investigation

Mykola Zdioruk:

ORCID: https://orcid.org/0000-0002-4275-2724

Role: Methodology

Sanghamitra Satpathi:

ORCID: https://orcid.org/0000-0003-0519-6199

Role: ResourcesRole: ValidationRole: Writing - review & editing

Prativa K. Behera:

ORCID: https://orcid.org/0000-0002-5435-3325

Role: InvestigationRole: Resources

Praveen K. Sahu:

ORCID: https://orcid.org/0000-0001-7855-7501

Role: InvestigationRole: Resources

Sean E. Lawler:

ORCID: https://orcid.org/0000-0002-1633-2339

Role: InvestigationRole: MethodologyRole: Writing - original draft

Klaus Qvortrup:

ORCID: https://orcid.org/0000-0001-8811-0260

Role: InvestigationRole: Writing - review & editing

Samuel C. Wassmer:

ORCID: https://orcid.org/0000-0002-6753-3376

Role: Funding acquisitionRole: InvestigationRole: ResourcesRole: Writing - original draft

Anja T.R. Jensen:

ORCID: https://orcid.org/0000-0002-4004-7554

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (iso-abbrev): J Exp Med

Journal ID (publisher-id): jem

Title: The Journal of Experimental Medicine

Publisher: Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date Collection: 01 March 2021

Publication date (Electronic): 25 January 2021

Publication date PMC-release: 25 January 2021

Volume: 218

Issue: 3

Electronic Location Identifier: e20201266

Affiliations

[1 ]Centre for Medical Parasitology at Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

[2 ]Brigham and Women’s Hospital, Boston, MA

[3 ]Harvard Medical School, Boston, MA

[4 ]Department of Pathology, Ispat General Hospital, Rourkela, India

[5 ]Center for the Study of Complex Malaria in India, Ispat General Hospital, Rourkela, India

[6 ]Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

[7 ]Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, UK

Author notes

Correspondence to Anja T.R. Jensen: atrj@ 123456sund.ku.dk

Yvonne Adams: yadams@ 123456sund.ku.dk

A. Bengtsson’s present address is Gubra, Hørsholm, Denmark.

S. Satpathi’s present address is Hitech Medical College and Hospital, Rourkela, India.

Author information

Yvonne Adams https://orcid.org/0000-0001-8041-6580

Rebecca W. Olsen https://orcid.org/0000-0003-4034-4302

Anja Bengtsson https://orcid.org/0000-0001-9523-8369

Nanna Dalgaard https://orcid.org/0000-0002-2584-9639

Mykola Zdioruk https://orcid.org/0000-0002-4275-2724

Sanghamitra Satpathi https://orcid.org/0000-0003-0519-6199

Prativa K. Behera https://orcid.org/0000-0002-5435-3325

Praveen K. Sahu https://orcid.org/0000-0001-7855-7501

Sean E. Lawler https://orcid.org/0000-0002-1633-2339

Klaus Qvortrup https://orcid.org/0000-0001-8811-0260

Samuel C. Wassmer https://orcid.org/0000-0002-6753-3376

Anja T.R. Jensen https://orcid.org/0000-0002-4004-7554

Article

Publisher ID: jem.20201266

DOI: 10.1084/jem.20201266

PMC ID: 7833209

PubMed ID: 33492344

SO-VID: 7b2c709d-0c78-4963-82d3-1f4111f0686e

License:

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

History

Date received : 19 June 2020

Date revision received : 11 November 2020

Date accepted : 11 December 2020

Page count

Pages: 13

Funding

Funded by: Augustinus Fonden, DOI http://dx.doi.org/10.13039/501100004954;

Funded by: Aase og Ejnar Danielsen Fond, DOI http://dx.doi.org/10.13039/501100003035;

Funded by: AP Møller Fonden;

Award ID: 18-L-0040

Funded by: Hørslev Fonden, DOI http://dx.doi.org/10.13039/100008733;

Award ID: 203866-MAS/mbs1

Funded by: Independent Research Fund Denmark, DOI http://dx.doi.org/10.13039/501100004836;

Award ID: 8020-00034B

Funded by: Lundbeck Foundation, DOI http://dx.doi.org/10.13039/501100003554;

Award ID: R180-2014-3098

Award ID: R324-2019-2029

Award ID: R313-2019-322

Funded by: Læge Sofus Carl Emil Friis og hustru Olga Doris Friis´ Legat, DOI http://dx.doi.org/10.13039/501100008269;

Funded by: Novo Nordisk Fonden, DOI http://dx.doi.org/10.13039/501100009708;

Award ID: NNF16OC0022298

Funded by: Svend Andersen Fonden, DOI http://dx.doi.org/10.13039/501100007371;

Funded by: Consultative Committee for Developmental Research;

Award ID: 17-02-KU

Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;

Award ID: RO1CA237063

Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;

Award ID: U19AI089676

Funded by: Medical Research Council, DOI http://dx.doi.org/10.13039/501100000265;

Plasmodium falciparum erythrocyte membrane protein 1 variants induce cell swelling and disrupt the blood–brain barrier in cerebral malaria

Read this article at

Abstract

Abstract

Graphical Abstract

Related collections

Probing cerebral hemodynamics with BOLD fMRI

Most cited references 59

Fiji: an open-source platform for biological-image analysis.

Tissue Plasminogen Activator for Acute Ischemic Stroke

Genome sequence of the human malaria parasite Plasmodium falciparum.

Author and article information

Contributors

Journal

Affiliations

Author notes

Author information

Article

History

Page count

Funding

Categories

Comments

Comment on this article

Similar content 361

Cited by 19

Most referenced authors 1,445