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Peptidoglycan editing in non-proliferating intracellular Salmonella as source of interference with immune signaling
Salmonella enterica causes intracellular infections that can be limited to the intestine or spread to deeper tissues. In most cases, intracellular bacteria show moderate growth. How these bacteria face host defenses that recognize peptidoglycan, is poorly understood. Here, we report a high-resolutio...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815878/ https://www.ncbi.nlm.nih.gov/pubmed/35077524 http://dx.doi.org/10.1371/journal.ppat.1010241 |
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author | Hernández, Sara B. Castanheira, Sónia Pucciarelli, M. Graciela Cestero, Juan J. Rico-Pérez, Gadea Paradela, Alberto Ayala, Juan A. Velázquez, Sonsoles San-Félix, Ana Cava, Felipe García-del Portillo, Francisco |
author_facet | Hernández, Sara B. Castanheira, Sónia Pucciarelli, M. Graciela Cestero, Juan J. Rico-Pérez, Gadea Paradela, Alberto Ayala, Juan A. Velázquez, Sonsoles San-Félix, Ana Cava, Felipe García-del Portillo, Francisco |
author_sort | Hernández, Sara B. |
collection | PubMed |
description | Salmonella enterica causes intracellular infections that can be limited to the intestine or spread to deeper tissues. In most cases, intracellular bacteria show moderate growth. How these bacteria face host defenses that recognize peptidoglycan, is poorly understood. Here, we report a high-resolution structural analysis of the minute amounts of peptidoglycan purified from S. enterica serovar Typhimurium (S. Typhimurium) infecting fibroblasts, a cell type in which this pathogen undergoes moderate growth and persists for days intracellularly. The peptidoglycan of these non-proliferating bacteria contains atypical crosslinked muropeptides with stem peptides trimmed at the L-alanine-D-glutamic acid-(γ) or D-glutamic acid-(γ)-meso-diaminopimelic acid motifs, both sensed by intracellular immune receptors. This peptidoglycan has a reduced glycan chain average length and ~30% increase in the L,D-crosslink, a type of bridge shared by all the atypical crosslinked muropeptides identified. The L,D-transpeptidases LdtD (YcbB) and LdtE (YnhG) are responsible for the formation of these L,D-bridges in the peptidoglycan of intracellular bacteria. We also identified in a fraction of muropeptides an unprecedented modification in the peptidoglycan of intracellular S. Typhimurium consisting of the amino alcohol alaninol replacing the terminal (fourth) D-alanine. Alaninol was still detectable in the peptidoglycan of a double mutant lacking LdtD and LdtE, thereby ruling out the contribution of these enzymes to this chemical modification. Remarkably, all multiple mutants tested lacking candidate enzymes that either trim stem peptides or form the L,D-bridges retain the capacity to modify the terminal D-alanine to alaninol and all attenuate NF-κB nuclear translocation. These data inferred a potential role of alaninol-containing muropeptides in attenuating pro-inflammatory signaling, which was confirmed with a synthetic tetrapeptide bearing such amino alcohol. We suggest that the modification of D-alanine to alaninol in the peptidoglycan of non-proliferating intracellular S. Typhimurium is an editing process exploited by this pathogen to evade immune recognition inside host cells. |
format | Online Article Text |
id | pubmed-8815878 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-88158782022-02-05 Peptidoglycan editing in non-proliferating intracellular Salmonella as source of interference with immune signaling Hernández, Sara B. Castanheira, Sónia Pucciarelli, M. Graciela Cestero, Juan J. Rico-Pérez, Gadea Paradela, Alberto Ayala, Juan A. Velázquez, Sonsoles San-Félix, Ana Cava, Felipe García-del Portillo, Francisco PLoS Pathog Research Article Salmonella enterica causes intracellular infections that can be limited to the intestine or spread to deeper tissues. In most cases, intracellular bacteria show moderate growth. How these bacteria face host defenses that recognize peptidoglycan, is poorly understood. Here, we report a high-resolution structural analysis of the minute amounts of peptidoglycan purified from S. enterica serovar Typhimurium (S. Typhimurium) infecting fibroblasts, a cell type in which this pathogen undergoes moderate growth and persists for days intracellularly. The peptidoglycan of these non-proliferating bacteria contains atypical crosslinked muropeptides with stem peptides trimmed at the L-alanine-D-glutamic acid-(γ) or D-glutamic acid-(γ)-meso-diaminopimelic acid motifs, both sensed by intracellular immune receptors. This peptidoglycan has a reduced glycan chain average length and ~30% increase in the L,D-crosslink, a type of bridge shared by all the atypical crosslinked muropeptides identified. The L,D-transpeptidases LdtD (YcbB) and LdtE (YnhG) are responsible for the formation of these L,D-bridges in the peptidoglycan of intracellular bacteria. We also identified in a fraction of muropeptides an unprecedented modification in the peptidoglycan of intracellular S. Typhimurium consisting of the amino alcohol alaninol replacing the terminal (fourth) D-alanine. Alaninol was still detectable in the peptidoglycan of a double mutant lacking LdtD and LdtE, thereby ruling out the contribution of these enzymes to this chemical modification. Remarkably, all multiple mutants tested lacking candidate enzymes that either trim stem peptides or form the L,D-bridges retain the capacity to modify the terminal D-alanine to alaninol and all attenuate NF-κB nuclear translocation. These data inferred a potential role of alaninol-containing muropeptides in attenuating pro-inflammatory signaling, which was confirmed with a synthetic tetrapeptide bearing such amino alcohol. We suggest that the modification of D-alanine to alaninol in the peptidoglycan of non-proliferating intracellular S. Typhimurium is an editing process exploited by this pathogen to evade immune recognition inside host cells. Public Library of Science 2022-01-25 /pmc/articles/PMC8815878/ /pubmed/35077524 http://dx.doi.org/10.1371/journal.ppat.1010241 Text en © 2022 Hernández et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://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 Hernández, Sara B. Castanheira, Sónia Pucciarelli, M. Graciela Cestero, Juan J. Rico-Pérez, Gadea Paradela, Alberto Ayala, Juan A. Velázquez, Sonsoles San-Félix, Ana Cava, Felipe García-del Portillo, Francisco Peptidoglycan editing in non-proliferating intracellular Salmonella as source of interference with immune signaling |
title | Peptidoglycan editing in non-proliferating intracellular Salmonella as source of interference with immune signaling |
title_full | Peptidoglycan editing in non-proliferating intracellular Salmonella as source of interference with immune signaling |
title_fullStr | Peptidoglycan editing in non-proliferating intracellular Salmonella as source of interference with immune signaling |
title_full_unstemmed | Peptidoglycan editing in non-proliferating intracellular Salmonella as source of interference with immune signaling |
title_short | Peptidoglycan editing in non-proliferating intracellular Salmonella as source of interference with immune signaling |
title_sort | peptidoglycan editing in non-proliferating intracellular salmonella as source of interference with immune signaling |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8815878/ https://www.ncbi.nlm.nih.gov/pubmed/35077524 http://dx.doi.org/10.1371/journal.ppat.1010241 |
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