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Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model

Chronic infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is a major contributor to progressive lung damage and is poorly treated by available antibiotic therapy. An alternative approach to the development of additional antibiotic treatments is to identify complementary therapies...

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Autores principales: Cigana, Cristina, Castandet, Jérôme, Sprynski, Nicolas, Melessike, Medede, Beyria, Lilha, Ranucci, Serena, Alcalá-Franco, Beatriz, Rossi, Alice, Bragonzi, Alessandra, Zalacain, Magdalena, Everett, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836092/
https://www.ncbi.nlm.nih.gov/pubmed/33510733
http://dx.doi.org/10.3389/fmicb.2020.620819
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author Cigana, Cristina
Castandet, Jérôme
Sprynski, Nicolas
Melessike, Medede
Beyria, Lilha
Ranucci, Serena
Alcalá-Franco, Beatriz
Rossi, Alice
Bragonzi, Alessandra
Zalacain, Magdalena
Everett, Martin
author_facet Cigana, Cristina
Castandet, Jérôme
Sprynski, Nicolas
Melessike, Medede
Beyria, Lilha
Ranucci, Serena
Alcalá-Franco, Beatriz
Rossi, Alice
Bragonzi, Alessandra
Zalacain, Magdalena
Everett, Martin
author_sort Cigana, Cristina
collection PubMed
description Chronic infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is a major contributor to progressive lung damage and is poorly treated by available antibiotic therapy. An alternative approach to the development of additional antibiotic treatments is to identify complementary therapies which target bacterial virulence factors necessary for the establishment and/or maintenance of the chronic infection. The P. aeruginosa elastase (LasB) has been suggested as an attractive anti-virulence target due to its extracellular location, its harmful degradative effects on host tissues and the immune system, and the potential to inhibit its activity using small molecule inhibitors. However, while the relevance of LasB in acute P. aeruginosa infection has been demonstrated, it is still unclear whether this elastase might also play a role in the early phase of chronic lung colonization. By analyzing clinical P. aeruginosa clonal isolates from a CF patient, we found that the isolate RP45, collected in the early phase of persistence, produces large amounts of active LasB, while its clonal variant RP73, collected after years of colonization, does not produce it. When a mouse model of persistent pneumonia was used, deletion of the lasB gene in RP45 resulted in a significant reduction in mean bacterial numbers and incidence of chronic lung colonization at Day 7 post-challenge compared to those mice infected with wild-type (wt) RP45. Furthermore, deletion of lasB in strain RP45 also resulted in an increase in immunomodulators associated with innate and adaptive immune responses in infected animals. In contrast, deletion of the lasB gene in RP73 did not affect the establishment of chronic infection. Overall, these results indicate that LasB contributes to the adaptation of P. aeruginosa to a persistent lifestyle. In addition, these findings support pharmacological inhibition of LasB as a potentially useful therapeutic intervention for P. aeruginosa-infected CF patients prior to the establishment of a chronic infection.
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spelling pubmed-78360922021-01-27 Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model Cigana, Cristina Castandet, Jérôme Sprynski, Nicolas Melessike, Medede Beyria, Lilha Ranucci, Serena Alcalá-Franco, Beatriz Rossi, Alice Bragonzi, Alessandra Zalacain, Magdalena Everett, Martin Front Microbiol Microbiology Chronic infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is a major contributor to progressive lung damage and is poorly treated by available antibiotic therapy. An alternative approach to the development of additional antibiotic treatments is to identify complementary therapies which target bacterial virulence factors necessary for the establishment and/or maintenance of the chronic infection. The P. aeruginosa elastase (LasB) has been suggested as an attractive anti-virulence target due to its extracellular location, its harmful degradative effects on host tissues and the immune system, and the potential to inhibit its activity using small molecule inhibitors. However, while the relevance of LasB in acute P. aeruginosa infection has been demonstrated, it is still unclear whether this elastase might also play a role in the early phase of chronic lung colonization. By analyzing clinical P. aeruginosa clonal isolates from a CF patient, we found that the isolate RP45, collected in the early phase of persistence, produces large amounts of active LasB, while its clonal variant RP73, collected after years of colonization, does not produce it. When a mouse model of persistent pneumonia was used, deletion of the lasB gene in RP45 resulted in a significant reduction in mean bacterial numbers and incidence of chronic lung colonization at Day 7 post-challenge compared to those mice infected with wild-type (wt) RP45. Furthermore, deletion of lasB in strain RP45 also resulted in an increase in immunomodulators associated with innate and adaptive immune responses in infected animals. In contrast, deletion of the lasB gene in RP73 did not affect the establishment of chronic infection. Overall, these results indicate that LasB contributes to the adaptation of P. aeruginosa to a persistent lifestyle. In addition, these findings support pharmacological inhibition of LasB as a potentially useful therapeutic intervention for P. aeruginosa-infected CF patients prior to the establishment of a chronic infection. Frontiers Media S.A. 2021-01-12 /pmc/articles/PMC7836092/ /pubmed/33510733 http://dx.doi.org/10.3389/fmicb.2020.620819 Text en Copyright © 2021 Cigana, Castandet, Sprynski, Melessike, Beyria, Ranucci, Alcalá-Franco, Rossi, Bragonzi, Zalacain and Everett. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Cigana, Cristina
Castandet, Jérôme
Sprynski, Nicolas
Melessike, Medede
Beyria, Lilha
Ranucci, Serena
Alcalá-Franco, Beatriz
Rossi, Alice
Bragonzi, Alessandra
Zalacain, Magdalena
Everett, Martin
Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model
title Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model
title_full Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model
title_fullStr Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model
title_full_unstemmed Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model
title_short Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model
title_sort pseudomonas aeruginosa elastase contributes to the establishment of chronic lung colonization and modulates the immune response in a murine model
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836092/
https://www.ncbi.nlm.nih.gov/pubmed/33510733
http://dx.doi.org/10.3389/fmicb.2020.620819
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