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Immunosuppression broadens evolutionary pathways to drug resistance and treatment failure during Acinetobacter baumannii pneumonia in mice

Acinetobacter baumannii is increasingly refractory to antibiotic treatment in healthcare settings. As is true of most human pathogens, the genetic path to antimicrobial resistance (AMR) and the role that the immune system plays in modulating AMR during disease are poorly understood. Here we reproduc...

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Autores principales: Huo, Wenwen, Busch, Lindsay M., Hernandez-Bird, Juan, Hamami, Efrat, Marshall, Christopher W., Geisinger, Edward, Cooper, Vaughn S., van Opijnen, Tim, Rosch, Jason W., Isberg, Ralph R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9159950/
https://www.ncbi.nlm.nih.gov/pubmed/35618774
http://dx.doi.org/10.1038/s41564-022-01126-8
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author Huo, Wenwen
Busch, Lindsay M.
Hernandez-Bird, Juan
Hamami, Efrat
Marshall, Christopher W.
Geisinger, Edward
Cooper, Vaughn S.
van Opijnen, Tim
Rosch, Jason W.
Isberg, Ralph R.
author_facet Huo, Wenwen
Busch, Lindsay M.
Hernandez-Bird, Juan
Hamami, Efrat
Marshall, Christopher W.
Geisinger, Edward
Cooper, Vaughn S.
van Opijnen, Tim
Rosch, Jason W.
Isberg, Ralph R.
author_sort Huo, Wenwen
collection PubMed
description Acinetobacter baumannii is increasingly refractory to antibiotic treatment in healthcare settings. As is true of most human pathogens, the genetic path to antimicrobial resistance (AMR) and the role that the immune system plays in modulating AMR during disease are poorly understood. Here we reproduced several routes to fluoroquinolone resistance, performing evolution experiments using sequential lung infections in mice that are replete with or depleted of neutrophils, providing two key insights into the evolution of drug resistance. First, neutropenic hosts acted as reservoirs for the accumulation of drug resistance during drug treatment. Selection for variants with altered drug sensitivity profiles arose readily in the absence of neutrophils, while immunocompetent animals restricted the appearance of these variants. Secondly, antibiotic treatment failure in the immunocompromised host was shown to occur without clinically defined resistance, an unexpected result that provides a model for how antibiotic failure occurs clinically in the absence of AMR. The genetic mechanism underlying both these results is initiated by mutations activating the drug egress pump regulator AdeL, which drives persistence in the presence of antibiotic. Therefore, antibiotic persistence mutations present a two-pronged risk during disease, causing drug treatment failure in the immunocompromised host while simultaneously increasing the emergence of high-level AMR.
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spelling pubmed-91599502022-06-03 Immunosuppression broadens evolutionary pathways to drug resistance and treatment failure during Acinetobacter baumannii pneumonia in mice Huo, Wenwen Busch, Lindsay M. Hernandez-Bird, Juan Hamami, Efrat Marshall, Christopher W. Geisinger, Edward Cooper, Vaughn S. van Opijnen, Tim Rosch, Jason W. Isberg, Ralph R. Nat Microbiol Article Acinetobacter baumannii is increasingly refractory to antibiotic treatment in healthcare settings. As is true of most human pathogens, the genetic path to antimicrobial resistance (AMR) and the role that the immune system plays in modulating AMR during disease are poorly understood. Here we reproduced several routes to fluoroquinolone resistance, performing evolution experiments using sequential lung infections in mice that are replete with or depleted of neutrophils, providing two key insights into the evolution of drug resistance. First, neutropenic hosts acted as reservoirs for the accumulation of drug resistance during drug treatment. Selection for variants with altered drug sensitivity profiles arose readily in the absence of neutrophils, while immunocompetent animals restricted the appearance of these variants. Secondly, antibiotic treatment failure in the immunocompromised host was shown to occur without clinically defined resistance, an unexpected result that provides a model for how antibiotic failure occurs clinically in the absence of AMR. The genetic mechanism underlying both these results is initiated by mutations activating the drug egress pump regulator AdeL, which drives persistence in the presence of antibiotic. Therefore, antibiotic persistence mutations present a two-pronged risk during disease, causing drug treatment failure in the immunocompromised host while simultaneously increasing the emergence of high-level AMR. Nature Publishing Group UK 2022-05-26 2022 /pmc/articles/PMC9159950/ /pubmed/35618774 http://dx.doi.org/10.1038/s41564-022-01126-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Huo, Wenwen
Busch, Lindsay M.
Hernandez-Bird, Juan
Hamami, Efrat
Marshall, Christopher W.
Geisinger, Edward
Cooper, Vaughn S.
van Opijnen, Tim
Rosch, Jason W.
Isberg, Ralph R.
Immunosuppression broadens evolutionary pathways to drug resistance and treatment failure during Acinetobacter baumannii pneumonia in mice
title Immunosuppression broadens evolutionary pathways to drug resistance and treatment failure during Acinetobacter baumannii pneumonia in mice
title_full Immunosuppression broadens evolutionary pathways to drug resistance and treatment failure during Acinetobacter baumannii pneumonia in mice
title_fullStr Immunosuppression broadens evolutionary pathways to drug resistance and treatment failure during Acinetobacter baumannii pneumonia in mice
title_full_unstemmed Immunosuppression broadens evolutionary pathways to drug resistance and treatment failure during Acinetobacter baumannii pneumonia in mice
title_short Immunosuppression broadens evolutionary pathways to drug resistance and treatment failure during Acinetobacter baumannii pneumonia in mice
title_sort immunosuppression broadens evolutionary pathways to drug resistance and treatment failure during acinetobacter baumannii pneumonia in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9159950/
https://www.ncbi.nlm.nih.gov/pubmed/35618774
http://dx.doi.org/10.1038/s41564-022-01126-8
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