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LipL21 lipoprotein binding to peptidoglycan enables Leptospira interrogans to escape NOD1 and NOD2 recognition

Leptospirosis is a widespread zoonosis, potentially severe in humans, caused by spirochetal bacteria, Leptospira interrogans (L. interrogans). Host defense mechanisms involved in leptospirosis are poorly understood. Recognition of lipopolysaccharide (LPS) and lipoproteins by Toll-Like Receptors (TLR...

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Autores principales: Ratet, Gwenn, Santecchia, Ignacio, Fanton d’Andon, Martine, Vernel-Pauillac, Frédérique, Wheeler, Richard, Lenormand, Pascal, Fischer, Frédéric, Lechat, Pierre, Haake, David A., Picardeau, Mathieu, Boneca, Ivo G., Werts, Catherine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764436/
https://www.ncbi.nlm.nih.gov/pubmed/29211798
http://dx.doi.org/10.1371/journal.ppat.1006725
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author Ratet, Gwenn
Santecchia, Ignacio
Fanton d’Andon, Martine
Vernel-Pauillac, Frédérique
Wheeler, Richard
Lenormand, Pascal
Fischer, Frédéric
Lechat, Pierre
Haake, David A.
Picardeau, Mathieu
Boneca, Ivo G.
Werts, Catherine
author_facet Ratet, Gwenn
Santecchia, Ignacio
Fanton d’Andon, Martine
Vernel-Pauillac, Frédérique
Wheeler, Richard
Lenormand, Pascal
Fischer, Frédéric
Lechat, Pierre
Haake, David A.
Picardeau, Mathieu
Boneca, Ivo G.
Werts, Catherine
author_sort Ratet, Gwenn
collection PubMed
description Leptospirosis is a widespread zoonosis, potentially severe in humans, caused by spirochetal bacteria, Leptospira interrogans (L. interrogans). Host defense mechanisms involved in leptospirosis are poorly understood. Recognition of lipopolysaccharide (LPS) and lipoproteins by Toll-Like Receptors (TLR)4 and TLR2 is crucial for clearance of leptospires in mice, yet the role of Nucleotide Oligomerization Domain (NOD)-like receptors (NOD)1 and NOD2, recognizing peptidoglycan (PG) fragments has not previously been examined. Here, we show that pathogenic leptospires escape from NOD1 and NOD2 recognition both in vitro and in vivo, in mice. We found that leptospiral PG is resistant to digestion by certain hydrolases and that a conserved outer membrane lipoprotein of unknown function, LipL21, specific for pathogenic leptospires, is tightly bound to the PG. Leptospiral PG prepared from a mutant not expressing LipL21 (lipl21(-)) was more readily digested than the parental or complemented strains. Muropeptides released from the PG of the lipl21(-) mutant, or prepared using a procedure to eliminate the LipL21 protein from the PG of the parental strain, were recognized in vitro by the human NOD1 (hNOD1) and NOD2 (hNOD2) receptors, suggesting that LipL21 protects PG from degradation into muropeptides. LipL21 expressed in E. coli also resulted in impaired PG digestion and NOD signaling. We found that murine NOD1 (mNOD1) did not recognize PG of L. interrogans. This result was confirmed by mass spectrometry showing that leptospiral PG was primarily composed of MurTriDAP, the natural agonist of hNOD1, and contained only trace amounts of the tetra muropeptide, the mNOD1 agonist. Finally, in transgenic mice expressing human NOD1 and deficient for the murine NOD1, we showed enhanced clearance of a lipl21(-) mutant compared to the complemented strain, or to what was observed in NOD1KO mice, suggesting that LipL21 facilitates escape from immune surveillance in humans. These novel mechanisms allowing L. interrogans to escape recognition by the NOD receptors may be important in circumventing innate host responses.
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spelling pubmed-57644362018-01-22 LipL21 lipoprotein binding to peptidoglycan enables Leptospira interrogans to escape NOD1 and NOD2 recognition Ratet, Gwenn Santecchia, Ignacio Fanton d’Andon, Martine Vernel-Pauillac, Frédérique Wheeler, Richard Lenormand, Pascal Fischer, Frédéric Lechat, Pierre Haake, David A. Picardeau, Mathieu Boneca, Ivo G. Werts, Catherine PLoS Pathog Research Article Leptospirosis is a widespread zoonosis, potentially severe in humans, caused by spirochetal bacteria, Leptospira interrogans (L. interrogans). Host defense mechanisms involved in leptospirosis are poorly understood. Recognition of lipopolysaccharide (LPS) and lipoproteins by Toll-Like Receptors (TLR)4 and TLR2 is crucial for clearance of leptospires in mice, yet the role of Nucleotide Oligomerization Domain (NOD)-like receptors (NOD)1 and NOD2, recognizing peptidoglycan (PG) fragments has not previously been examined. Here, we show that pathogenic leptospires escape from NOD1 and NOD2 recognition both in vitro and in vivo, in mice. We found that leptospiral PG is resistant to digestion by certain hydrolases and that a conserved outer membrane lipoprotein of unknown function, LipL21, specific for pathogenic leptospires, is tightly bound to the PG. Leptospiral PG prepared from a mutant not expressing LipL21 (lipl21(-)) was more readily digested than the parental or complemented strains. Muropeptides released from the PG of the lipl21(-) mutant, or prepared using a procedure to eliminate the LipL21 protein from the PG of the parental strain, were recognized in vitro by the human NOD1 (hNOD1) and NOD2 (hNOD2) receptors, suggesting that LipL21 protects PG from degradation into muropeptides. LipL21 expressed in E. coli also resulted in impaired PG digestion and NOD signaling. We found that murine NOD1 (mNOD1) did not recognize PG of L. interrogans. This result was confirmed by mass spectrometry showing that leptospiral PG was primarily composed of MurTriDAP, the natural agonist of hNOD1, and contained only trace amounts of the tetra muropeptide, the mNOD1 agonist. Finally, in transgenic mice expressing human NOD1 and deficient for the murine NOD1, we showed enhanced clearance of a lipl21(-) mutant compared to the complemented strain, or to what was observed in NOD1KO mice, suggesting that LipL21 facilitates escape from immune surveillance in humans. These novel mechanisms allowing L. interrogans to escape recognition by the NOD receptors may be important in circumventing innate host responses. Public Library of Science 2017-12-06 /pmc/articles/PMC5764436/ /pubmed/29211798 http://dx.doi.org/10.1371/journal.ppat.1006725 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Ratet, Gwenn
Santecchia, Ignacio
Fanton d’Andon, Martine
Vernel-Pauillac, Frédérique
Wheeler, Richard
Lenormand, Pascal
Fischer, Frédéric
Lechat, Pierre
Haake, David A.
Picardeau, Mathieu
Boneca, Ivo G.
Werts, Catherine
LipL21 lipoprotein binding to peptidoglycan enables Leptospira interrogans to escape NOD1 and NOD2 recognition
title LipL21 lipoprotein binding to peptidoglycan enables Leptospira interrogans to escape NOD1 and NOD2 recognition
title_full LipL21 lipoprotein binding to peptidoglycan enables Leptospira interrogans to escape NOD1 and NOD2 recognition
title_fullStr LipL21 lipoprotein binding to peptidoglycan enables Leptospira interrogans to escape NOD1 and NOD2 recognition
title_full_unstemmed LipL21 lipoprotein binding to peptidoglycan enables Leptospira interrogans to escape NOD1 and NOD2 recognition
title_short LipL21 lipoprotein binding to peptidoglycan enables Leptospira interrogans to escape NOD1 and NOD2 recognition
title_sort lipl21 lipoprotein binding to peptidoglycan enables leptospira interrogans to escape nod1 and nod2 recognition
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764436/
https://www.ncbi.nlm.nih.gov/pubmed/29211798
http://dx.doi.org/10.1371/journal.ppat.1006725
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