Cargando…

Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria

Malaria during pregnancy results in intrauterine growth restriction, fetal anemia, and infant mortality. Women are more susceptible to malaria during pregnancy due to malaria‐induced inflammation and the sequestration of infected red blood cells in the placenta, which bind to the chondroitin sulfate...

Descripción completa

Detalles Bibliográficos
Autor principal: Clark, Robert L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432169/
https://www.ncbi.nlm.nih.gov/pubmed/30919596
http://dx.doi.org/10.1002/bdr2.1496
_version_ 1783571738052788224
author Clark, Robert L.
author_facet Clark, Robert L.
author_sort Clark, Robert L.
collection PubMed
description Malaria during pregnancy results in intrauterine growth restriction, fetal anemia, and infant mortality. Women are more susceptible to malaria during pregnancy due to malaria‐induced inflammation and the sequestration of infected red blood cells in the placenta, which bind to the chondroitin sulfate portion of syndecan‐1 on the syncytiotrophoblast and in the intervillous space. Syndecan‐1 is a dimeric proteoglycan with an extracellular ectodomain that is cleaved from the transmembrane domain (referred to as “shedding”) by matrix metalloproteinases (MMPs), likely the secreted MMP‐9. The ectodomain includes four binding sites for chondroitin sulfate, which are proximal to the transmembrane domain, and six distal binding sites primarily for heparan sulfate. This “shedding” of syndecan‐1 is inhibited by the presence of the heparan sulfate chains, which can be removed by heparanase. The intervillous space contains fibrin strands and syndecan‐1 ectodomains free of heparan sulfate. The following is proposed as the sequence of events that leads to and is primarily responsible for sequestration in the intervillous space of the placenta. Inflammation associated with malaria triggers increased heparanase activity that degrades the heparan sulfate on the membrane‐bound syndecan‐1. Inflammation also upregulates MMP‐9 and the removal of heparan sulfate gives MMP‐9 access to cleave syndecan‐1, thereby releasing dimeric syndecan‐1 ectodomains with at least four chondroitin sulfate chains attached. These multivalent ectodomains bind infected RBCs together leading to their aggregation and entrapment in intervillous fibrin. This mechanism suggests possible new targets for anti‐placental malaria drugs such as the inhibition of MMP‐9. Doxycycline is an antimalarial drug which inhibits MMP‐9.
format Online
Article
Text
id pubmed-7432169
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher John Wiley & Sons, Inc.
record_format MEDLINE/PubMed
spelling pubmed-74321692020-08-20 Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria Clark, Robert L. Birth Defects Res Review Article Malaria during pregnancy results in intrauterine growth restriction, fetal anemia, and infant mortality. Women are more susceptible to malaria during pregnancy due to malaria‐induced inflammation and the sequestration of infected red blood cells in the placenta, which bind to the chondroitin sulfate portion of syndecan‐1 on the syncytiotrophoblast and in the intervillous space. Syndecan‐1 is a dimeric proteoglycan with an extracellular ectodomain that is cleaved from the transmembrane domain (referred to as “shedding”) by matrix metalloproteinases (MMPs), likely the secreted MMP‐9. The ectodomain includes four binding sites for chondroitin sulfate, which are proximal to the transmembrane domain, and six distal binding sites primarily for heparan sulfate. This “shedding” of syndecan‐1 is inhibited by the presence of the heparan sulfate chains, which can be removed by heparanase. The intervillous space contains fibrin strands and syndecan‐1 ectodomains free of heparan sulfate. The following is proposed as the sequence of events that leads to and is primarily responsible for sequestration in the intervillous space of the placenta. Inflammation associated with malaria triggers increased heparanase activity that degrades the heparan sulfate on the membrane‐bound syndecan‐1. Inflammation also upregulates MMP‐9 and the removal of heparan sulfate gives MMP‐9 access to cleave syndecan‐1, thereby releasing dimeric syndecan‐1 ectodomains with at least four chondroitin sulfate chains attached. These multivalent ectodomains bind infected RBCs together leading to their aggregation and entrapment in intervillous fibrin. This mechanism suggests possible new targets for anti‐placental malaria drugs such as the inhibition of MMP‐9. Doxycycline is an antimalarial drug which inhibits MMP‐9. John Wiley & Sons, Inc. 2019-03-28 2019-06-01 /pmc/articles/PMC7432169/ /pubmed/30919596 http://dx.doi.org/10.1002/bdr2.1496 Text en © 2019 The Author. Birth Defects Research published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review Article
Clark, Robert L.
Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria
title Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria
title_full Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria
title_fullStr Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria
title_full_unstemmed Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria
title_short Genesis of placental sequestration in malaria and possible targets for drugs for placental malaria
title_sort genesis of placental sequestration in malaria and possible targets for drugs for placental malaria
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432169/
https://www.ncbi.nlm.nih.gov/pubmed/30919596
http://dx.doi.org/10.1002/bdr2.1496
work_keys_str_mv AT clarkrobertl genesisofplacentalsequestrationinmalariaandpossibletargetsfordrugsforplacentalmalaria