Cargando…
Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan
Severe human malaria is attributable to an excessive sequestration of Plasmodium falciparum–infected and uninfected erythrocytes in vital organs. Strains of P. falciparum that form rosettes and employ heparan sulfate as a host receptor are associated with development of severe forms of malaria. Hepa...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2006
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1579244/ https://www.ncbi.nlm.nih.gov/pubmed/17009869 http://dx.doi.org/10.1371/journal.ppat.0020100 |
_version_ | 1782130318123204608 |
---|---|
author | Vogt, Anna M Pettersson, Fredrik Moll, Kirsten Jonsson, Cathrine Normark, Johan Ribacke, Ulf Egwang, Thomas G Ekre, Hans-Peter Spillmann, Dorothe Chen, Qijun Wahlgren, Mats |
author_facet | Vogt, Anna M Pettersson, Fredrik Moll, Kirsten Jonsson, Cathrine Normark, Johan Ribacke, Ulf Egwang, Thomas G Ekre, Hans-Peter Spillmann, Dorothe Chen, Qijun Wahlgren, Mats |
author_sort | Vogt, Anna M |
collection | PubMed |
description | Severe human malaria is attributable to an excessive sequestration of Plasmodium falciparum–infected and uninfected erythrocytes in vital organs. Strains of P. falciparum that form rosettes and employ heparan sulfate as a host receptor are associated with development of severe forms of malaria. Heparin, which is similar to heparan sulfate in that it is composed of the same building blocks, was previously used in the treatment of severe malaria, but it was discontinued due to the occurrence of serious side effects such as intracranial bleedings. Here we report to have depolymerized heparin by periodate treatment to generate novel glycans (dGAG) that lack anticoagulant-activity. The dGAGs disrupt rosettes, inhibit merozoite invasion of erythrocytes and endothelial binding of P. falciparum–infected erythrocytes in vitro, and reduce sequestration in in vivo models of severe malaria. An intravenous injection of dGAGs blocks up to 80% of infected erythrocytes from binding in the micro-vasculature of the rat and releases already sequestered parasites into circulation. P. falciparum–infected human erythrocytes that sequester in the non-human primate Macaca fascicularis were similarly found to be released in to the circulation upon a single injection of 500 μg of dGAG. We suggest dGAGs to be promising candidates for adjunct therapy in severe malaria. |
format | Text |
id | pubmed-1579244 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2006 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-15792442006-10-05 Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan Vogt, Anna M Pettersson, Fredrik Moll, Kirsten Jonsson, Cathrine Normark, Johan Ribacke, Ulf Egwang, Thomas G Ekre, Hans-Peter Spillmann, Dorothe Chen, Qijun Wahlgren, Mats PLoS Pathog Research Article Severe human malaria is attributable to an excessive sequestration of Plasmodium falciparum–infected and uninfected erythrocytes in vital organs. Strains of P. falciparum that form rosettes and employ heparan sulfate as a host receptor are associated with development of severe forms of malaria. Heparin, which is similar to heparan sulfate in that it is composed of the same building blocks, was previously used in the treatment of severe malaria, but it was discontinued due to the occurrence of serious side effects such as intracranial bleedings. Here we report to have depolymerized heparin by periodate treatment to generate novel glycans (dGAG) that lack anticoagulant-activity. The dGAGs disrupt rosettes, inhibit merozoite invasion of erythrocytes and endothelial binding of P. falciparum–infected erythrocytes in vitro, and reduce sequestration in in vivo models of severe malaria. An intravenous injection of dGAGs blocks up to 80% of infected erythrocytes from binding in the micro-vasculature of the rat and releases already sequestered parasites into circulation. P. falciparum–infected human erythrocytes that sequester in the non-human primate Macaca fascicularis were similarly found to be released in to the circulation upon a single injection of 500 μg of dGAG. We suggest dGAGs to be promising candidates for adjunct therapy in severe malaria. Public Library of Science 2006-09 2006-09-29 /pmc/articles/PMC1579244/ /pubmed/17009869 http://dx.doi.org/10.1371/journal.ppat.0020100 Text en © 2006 Vogt et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Vogt, Anna M Pettersson, Fredrik Moll, Kirsten Jonsson, Cathrine Normark, Johan Ribacke, Ulf Egwang, Thomas G Ekre, Hans-Peter Spillmann, Dorothe Chen, Qijun Wahlgren, Mats Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan |
title | Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan |
title_full | Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan |
title_fullStr | Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan |
title_full_unstemmed | Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan |
title_short | Release of Sequestered Malaria Parasites upon Injection of a Glycosaminoglycan |
title_sort | release of sequestered malaria parasites upon injection of a glycosaminoglycan |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1579244/ https://www.ncbi.nlm.nih.gov/pubmed/17009869 http://dx.doi.org/10.1371/journal.ppat.0020100 |
work_keys_str_mv | AT vogtannam releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan AT petterssonfredrik releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan AT mollkirsten releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan AT jonssoncathrine releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan AT normarkjohan releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan AT ribackeulf releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan AT egwangthomasg releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan AT ekrehanspeter releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan AT spillmanndorothe releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan AT chenqijun releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan AT wahlgrenmats releaseofsequesteredmalariaparasitesuponinjectionofaglycosaminoglycan |