Investigating the function of Fc‐specific binding of IgM to P lasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting

Investigating the function of Fc‐specific binding of IgM to P lasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting

Acquired protection from P lasmodium falciparum malaria takes years to develop, probably reflecting the ability of the parasites to evade immunity. A recent example of this is the binding of the Fc region of IgM to VAR2CSA‐type PfEMP1. This interferes with specific IgG recognition and phagocytosis o...

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Main Authors: Stevenson, Liz, Huda, Pie, Jeppesen, Anine, Laursen, Erik, Rowe, J. Alexandra, Craig, Alister, Streicher, Werner, Barfod, Lea, Hviid, Lars
Format: Online
Language:English
Published: John Wiley and Sons Inc. 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737123/
id pubmed-4737123
recordtype oai_dc
spelling pubmed-47371232016-02-11 Investigating the function of Fc‐specific binding of IgM to P lasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting Stevenson, Liz Huda, Pie Jeppesen, Anine Laursen, Erik Rowe, J. Alexandra Craig, Alister Streicher, Werner Barfod, Lea Hviid, Lars Original Articles Acquired protection from P lasmodium falciparum malaria takes years to develop, probably reflecting the ability of the parasites to evade immunity. A recent example of this is the binding of the Fc region of IgM to VAR2CSA‐type PfEMP1. This interferes with specific IgG recognition and phagocytosis of opsonized infected erythrocytes (IEs) without compromising the placental IE adhesion mediated by this PfEMP1 type. IgM also binds via Fc to several other PfEMP1 proteins, where it has been proposed to facilitate rosetting (binding of uninfected erythrocytes to a central IE). To further dissect the functional role of Fc‐mediated IgM binding to PfEMP1, we studied the PfEMP1 protein HB3VAR06, which mediates rosetting and binds IgM. Binding of IgM to this PfEMP1 involved the Fc domains Cμ3‐Cμ4 in IgM and the penultimate DBL domain (DBLζ2) at the C‐terminus of HB3VAR06. However, IgM binding did not inhibit specific IgG labelling of HB3VAR06 or shield IgG‐opsonized IEs from phagocytosis. Instead, IgM was required for rosetting, and each pentameric IgM molecule could bind two HB3VAR06 molecules. Together, our data indicate that the primary function of Fc‐mediated IgM binding in rosetting is not to shield IE from specific IgG recognition and phagocytosis as in VAR2CSA‐type PfEMP1. Rather, the function appears to be strengthening of IE–erythrocyte interactions. In conclusion, our study provides new evidence on the molecular details and functional significance of rosetting, a long‐recognized marker of parasites that cause severe P . falciparum malaria. John Wiley and Sons Inc. 2015-01-28 2015-06 /pmc/articles/PMC4737123/ /pubmed/25482886 http://dx.doi.org/10.1111/cmi.12403 Text en © 2014 The Authors. Cellular Microbiology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Stevenson, Liz
Huda, Pie
Jeppesen, Anine
Laursen, Erik
Rowe, J. Alexandra
Craig, Alister
Streicher, Werner
Barfod, Lea
Hviid, Lars
spellingShingle Stevenson, Liz
Huda, Pie
Jeppesen, Anine
Laursen, Erik
Rowe, J. Alexandra
Craig, Alister
Streicher, Werner
Barfod, Lea
Hviid, Lars
Investigating the function of Fc‐specific binding of IgM to P lasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting
author_facet Stevenson, Liz
Huda, Pie
Jeppesen, Anine
Laursen, Erik
Rowe, J. Alexandra
Craig, Alister
Streicher, Werner
Barfod, Lea
Hviid, Lars
author_sort Stevenson, Liz
title Investigating the function of Fc‐specific binding of IgM to P lasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting
title_short Investigating the function of Fc‐specific binding of IgM to P lasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting
title_full Investigating the function of Fc‐specific binding of IgM to P lasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting
title_fullStr Investigating the function of Fc‐specific binding of IgM to P lasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting
title_full_unstemmed Investigating the function of Fc‐specific binding of IgM to P lasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting
title_sort investigating the function of fc‐specific binding of igm to p lasmodium falciparum erythrocyte membrane protein 1 mediating erythrocyte rosetting
description Acquired protection from P lasmodium falciparum malaria takes years to develop, probably reflecting the ability of the parasites to evade immunity. A recent example of this is the binding of the Fc region of IgM to VAR2CSA‐type PfEMP1. This interferes with specific IgG recognition and phagocytosis of opsonized infected erythrocytes (IEs) without compromising the placental IE adhesion mediated by this PfEMP1 type. IgM also binds via Fc to several other PfEMP1 proteins, where it has been proposed to facilitate rosetting (binding of uninfected erythrocytes to a central IE). To further dissect the functional role of Fc‐mediated IgM binding to PfEMP1, we studied the PfEMP1 protein HB3VAR06, which mediates rosetting and binds IgM. Binding of IgM to this PfEMP1 involved the Fc domains Cμ3‐Cμ4 in IgM and the penultimate DBL domain (DBLζ2) at the C‐terminus of HB3VAR06. However, IgM binding did not inhibit specific IgG labelling of HB3VAR06 or shield IgG‐opsonized IEs from phagocytosis. Instead, IgM was required for rosetting, and each pentameric IgM molecule could bind two HB3VAR06 molecules. Together, our data indicate that the primary function of Fc‐mediated IgM binding in rosetting is not to shield IE from specific IgG recognition and phagocytosis as in VAR2CSA‐type PfEMP1. Rather, the function appears to be strengthening of IE–erythrocyte interactions. In conclusion, our study provides new evidence on the molecular details and functional significance of rosetting, a long‐recognized marker of parasites that cause severe P . falciparum malaria.
publisher John Wiley and Sons Inc.
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737123/
_version_ 1613532278351200256

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