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Antibody-Mediated Immobilization of Virions in Mucus

Antibodies have been shown to hinder the movement of herpes simplex virus virions in cervicovaginal mucus, as well as other viruses in other mucus secretions. However, it has not been possible to directly observe the mechanisms underlying this phenomenon, so the nature of virion–antibody–mucin inter...

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Autores principales: Jensen, Melanie A., Wang, Ying-Ying, Lai, Samuel K., Forest, M. Gregory, McKinley, Scott A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764938/
https://www.ncbi.nlm.nih.gov/pubmed/31468263
http://dx.doi.org/10.1007/s11538-019-00653-6
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author Jensen, Melanie A.
Wang, Ying-Ying
Lai, Samuel K.
Forest, M. Gregory
McKinley, Scott A.
author_facet Jensen, Melanie A.
Wang, Ying-Ying
Lai, Samuel K.
Forest, M. Gregory
McKinley, Scott A.
author_sort Jensen, Melanie A.
collection PubMed
description Antibodies have been shown to hinder the movement of herpes simplex virus virions in cervicovaginal mucus, as well as other viruses in other mucus secretions. However, it has not been possible to directly observe the mechanisms underlying this phenomenon, so the nature of virion–antibody–mucin interactions remain poorly understood. In this work, we analyzed thousands of virion traces from single particle tracking experiments to explicate how antibodies must cooperate to immobilize virions for relatively long time periods. First, using a clustering analysis, we observed a clear separation between two classes of virion behavior: freely diffusing and immobilized. While the proportion of freely diffusing virions decreased with antibody concentration, the magnitude of their diffusivity did not, implying an all-or-nothing dichotomy in the pathwise effect of the antibodies. Proceeding under the assumption that all binding events are reversible, we used a novel switch-point detection method to conclude that there are very few, if any, state switches on the experimental timescale of 20 s. To understand this slow state switching, we analyzed a recently proposed continuous-time Markov chain model for binding kinetics and virion movement. Model analysis implied that virion immobilization requires cooperation by multiple antibodies that are simultaneously bound to the virion and mucin matrix and that there is an entanglement phenomenon that accelerates antibody–mucin binding when a virion is immobilized. In addition to developing a widely applicable framework for analyzing multistate particle behavior, this work substantially enhances our mechanistic understanding of how antibodies can reinforce a mucus barrier against passive invasive species. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11538-019-00653-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-67649382019-10-07 Antibody-Mediated Immobilization of Virions in Mucus Jensen, Melanie A. Wang, Ying-Ying Lai, Samuel K. Forest, M. Gregory McKinley, Scott A. Bull Math Biol Original Article Antibodies have been shown to hinder the movement of herpes simplex virus virions in cervicovaginal mucus, as well as other viruses in other mucus secretions. However, it has not been possible to directly observe the mechanisms underlying this phenomenon, so the nature of virion–antibody–mucin interactions remain poorly understood. In this work, we analyzed thousands of virion traces from single particle tracking experiments to explicate how antibodies must cooperate to immobilize virions for relatively long time periods. First, using a clustering analysis, we observed a clear separation between two classes of virion behavior: freely diffusing and immobilized. While the proportion of freely diffusing virions decreased with antibody concentration, the magnitude of their diffusivity did not, implying an all-or-nothing dichotomy in the pathwise effect of the antibodies. Proceeding under the assumption that all binding events are reversible, we used a novel switch-point detection method to conclude that there are very few, if any, state switches on the experimental timescale of 20 s. To understand this slow state switching, we analyzed a recently proposed continuous-time Markov chain model for binding kinetics and virion movement. Model analysis implied that virion immobilization requires cooperation by multiple antibodies that are simultaneously bound to the virion and mucin matrix and that there is an entanglement phenomenon that accelerates antibody–mucin binding when a virion is immobilized. In addition to developing a widely applicable framework for analyzing multistate particle behavior, this work substantially enhances our mechanistic understanding of how antibodies can reinforce a mucus barrier against passive invasive species. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11538-019-00653-6) contains supplementary material, which is available to authorized users. Springer US 2019-08-29 2019 /pmc/articles/PMC6764938/ /pubmed/31468263 http://dx.doi.org/10.1007/s11538-019-00653-6 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Jensen, Melanie A.
Wang, Ying-Ying
Lai, Samuel K.
Forest, M. Gregory
McKinley, Scott A.
Antibody-Mediated Immobilization of Virions in Mucus
title Antibody-Mediated Immobilization of Virions in Mucus
title_full Antibody-Mediated Immobilization of Virions in Mucus
title_fullStr Antibody-Mediated Immobilization of Virions in Mucus
title_full_unstemmed Antibody-Mediated Immobilization of Virions in Mucus
title_short Antibody-Mediated Immobilization of Virions in Mucus
title_sort antibody-mediated immobilization of virions in mucus
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764938/
https://www.ncbi.nlm.nih.gov/pubmed/31468263
http://dx.doi.org/10.1007/s11538-019-00653-6
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