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Outer membrane permeabilization by the membrane attack complex sensitizes Gram-negative bacteria to antimicrobial proteins in serum and phagocytes

Infections with Gram-negative bacteria form an increasing risk for human health due to antibiotic resistance. Our immune system contains various antimicrobial proteins that can degrade the bacterial cell envelope. However, many of these proteins do not function on Gram-negative bacteria, because the...

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Autores principales: Heesterbeek, Dani A. C., Muts, Remy M., van Hensbergen, Vincent P., de Saint Aulaire, Pieter, Wennekes, Tom, Bardoel, Bart W., van Sorge, Nina M., Rooijakkers, Suzan H. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886145/
https://www.ncbi.nlm.nih.gov/pubmed/33481964
http://dx.doi.org/10.1371/journal.ppat.1009227
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author Heesterbeek, Dani A. C.
Muts, Remy M.
van Hensbergen, Vincent P.
de Saint Aulaire, Pieter
Wennekes, Tom
Bardoel, Bart W.
van Sorge, Nina M.
Rooijakkers, Suzan H. M.
author_facet Heesterbeek, Dani A. C.
Muts, Remy M.
van Hensbergen, Vincent P.
de Saint Aulaire, Pieter
Wennekes, Tom
Bardoel, Bart W.
van Sorge, Nina M.
Rooijakkers, Suzan H. M.
author_sort Heesterbeek, Dani A. C.
collection PubMed
description Infections with Gram-negative bacteria form an increasing risk for human health due to antibiotic resistance. Our immune system contains various antimicrobial proteins that can degrade the bacterial cell envelope. However, many of these proteins do not function on Gram-negative bacteria, because the impermeable outer membrane of these bacteria prevents such components from reaching their targets. Here we show that complement-dependent formation of Membrane Attack Complex (MAC) pores permeabilizes this barrier, allowing antimicrobial proteins to cross the outer membrane and exert their antimicrobial function. Specifically, we demonstrate that MAC-dependent outer membrane damage enables human lysozyme to degrade the cell wall of E. coli. Using flow cytometry and confocal microscopy, we show that the combination of MAC pores and lysozyme triggers effective E. coli cell wall degradation in human serum, thereby altering the bacterial cell morphology from rod-shaped to spherical. Completely assembled MAC pores are required to sensitize E. coli to the antimicrobial actions of lysozyme and other immune factors, such as Human Group IIA-secreted Phospholipase A2. Next to these effects in a serum environment, we observed that the MAC also sensitizes E. coli to more efficient degradation and killing inside human neutrophils. Altogether, this study serves as a proof of principle on how different players of the human immune system can work together to degrade the complex cell envelope of Gram-negative bacteria. This knowledge may facilitate the development of new antimicrobials that could stimulate or work synergistically with the immune system.
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spelling pubmed-78861452021-02-23 Outer membrane permeabilization by the membrane attack complex sensitizes Gram-negative bacteria to antimicrobial proteins in serum and phagocytes Heesterbeek, Dani A. C. Muts, Remy M. van Hensbergen, Vincent P. de Saint Aulaire, Pieter Wennekes, Tom Bardoel, Bart W. van Sorge, Nina M. Rooijakkers, Suzan H. M. PLoS Pathog Research Article Infections with Gram-negative bacteria form an increasing risk for human health due to antibiotic resistance. Our immune system contains various antimicrobial proteins that can degrade the bacterial cell envelope. However, many of these proteins do not function on Gram-negative bacteria, because the impermeable outer membrane of these bacteria prevents such components from reaching their targets. Here we show that complement-dependent formation of Membrane Attack Complex (MAC) pores permeabilizes this barrier, allowing antimicrobial proteins to cross the outer membrane and exert their antimicrobial function. Specifically, we demonstrate that MAC-dependent outer membrane damage enables human lysozyme to degrade the cell wall of E. coli. Using flow cytometry and confocal microscopy, we show that the combination of MAC pores and lysozyme triggers effective E. coli cell wall degradation in human serum, thereby altering the bacterial cell morphology from rod-shaped to spherical. Completely assembled MAC pores are required to sensitize E. coli to the antimicrobial actions of lysozyme and other immune factors, such as Human Group IIA-secreted Phospholipase A2. Next to these effects in a serum environment, we observed that the MAC also sensitizes E. coli to more efficient degradation and killing inside human neutrophils. Altogether, this study serves as a proof of principle on how different players of the human immune system can work together to degrade the complex cell envelope of Gram-negative bacteria. This knowledge may facilitate the development of new antimicrobials that could stimulate or work synergistically with the immune system. Public Library of Science 2021-01-22 /pmc/articles/PMC7886145/ /pubmed/33481964 http://dx.doi.org/10.1371/journal.ppat.1009227 Text en © 2021 Heesterbeek 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 (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Heesterbeek, Dani A. C.
Muts, Remy M.
van Hensbergen, Vincent P.
de Saint Aulaire, Pieter
Wennekes, Tom
Bardoel, Bart W.
van Sorge, Nina M.
Rooijakkers, Suzan H. M.
Outer membrane permeabilization by the membrane attack complex sensitizes Gram-negative bacteria to antimicrobial proteins in serum and phagocytes
title Outer membrane permeabilization by the membrane attack complex sensitizes Gram-negative bacteria to antimicrobial proteins in serum and phagocytes
title_full Outer membrane permeabilization by the membrane attack complex sensitizes Gram-negative bacteria to antimicrobial proteins in serum and phagocytes
title_fullStr Outer membrane permeabilization by the membrane attack complex sensitizes Gram-negative bacteria to antimicrobial proteins in serum and phagocytes
title_full_unstemmed Outer membrane permeabilization by the membrane attack complex sensitizes Gram-negative bacteria to antimicrobial proteins in serum and phagocytes
title_short Outer membrane permeabilization by the membrane attack complex sensitizes Gram-negative bacteria to antimicrobial proteins in serum and phagocytes
title_sort outer membrane permeabilization by the membrane attack complex sensitizes gram-negative bacteria to antimicrobial proteins in serum and phagocytes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886145/
https://www.ncbi.nlm.nih.gov/pubmed/33481964
http://dx.doi.org/10.1371/journal.ppat.1009227
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