Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media

Abstract Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly understood immunology. Here, we assess the host response to middle ear infection over the course of a month post-infection in a mouse model of CSOM and in human subjects with the disease. Using multipa...

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Autores principales:	K. M. Khomtchouk, L. I. Joseph, B. B. Khomtchouk, A. Kouhi, S. Massa, A. Xia, I. Koliesnik, D. Pletzer, P. L. Bollyky, P. L. Santa Maria
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Microbial ecology QR100-130
Acceso en línea:	https://doaj.org/article/7b834c89fd354cdaa19d65fb3bc5042d
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spelling	oai:doaj.org-article:7b834c89fd354cdaa19d65fb3bc5042d2021-12-02T18:15:35ZTreatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media10.1038/s41522-021-00200-z2055-5008https://doaj.org/article/7b834c89fd354cdaa19d65fb3bc5042d2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41522-021-00200-zhttps://doaj.org/toc/2055-5008Abstract Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly understood immunology. Here, we assess the host response to middle ear infection over the course of a month post-infection in a mouse model of CSOM and in human subjects with the disease. Using multiparameter flow cytometry and a binomial generalized linear machine learning model, we identified Ly6G, a surface marker of mature neutrophils, as the most informative factor of host response driving disease in the CSOM mouse model. Consistent with this, neutrophils were the most abundant cell type in infected mice and Ly6G expression tracked with the course of infection. Moreover, neutrophil-specific immunomodulatory treatment using the neutrophil elastase inhibitor GW 311616A significantly reduces bacterial burden relative to ofloxacin-only treated animals in this model. The levels of dsDNA in middle ear effusion samples are elevated in both humans and mice with CSOM and decreased during treatment, suggesting that dsDNA may serve as a molecular biomarker of treatment response. Together these data strongly implicate neutrophils in the ineffective immune response to P. aeruginosa infection in CSOM and suggest that immunomodulatory strategies may benefit drug-tolerant infections for chronic biofilm-mediated disease.K. M. KhomtchoukL. I. JosephB. B. KhomtchoukA. KouhiS. MassaA. XiaI. KoliesnikD. PletzerP. L. BollykyP. L. Santa MariaNature PortfolioarticleMicrobial ecologyQR100-130ENnpj Biofilms and Microbiomes, Vol 7, Iss 1, Pp 1-8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbial ecology QR100-130
spellingShingle	Microbial ecology QR100-130 K. M. Khomtchouk L. I. Joseph B. B. Khomtchouk A. Kouhi S. Massa A. Xia I. Koliesnik D. Pletzer P. L. Bollyky P. L. Santa Maria Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media
description	Abstract Chronic suppurative otitis media (CSOM) is a widespread, debilitating problem with poorly understood immunology. Here, we assess the host response to middle ear infection over the course of a month post-infection in a mouse model of CSOM and in human subjects with the disease. Using multiparameter flow cytometry and a binomial generalized linear machine learning model, we identified Ly6G, a surface marker of mature neutrophils, as the most informative factor of host response driving disease in the CSOM mouse model. Consistent with this, neutrophils were the most abundant cell type in infected mice and Ly6G expression tracked with the course of infection. Moreover, neutrophil-specific immunomodulatory treatment using the neutrophil elastase inhibitor GW 311616A significantly reduces bacterial burden relative to ofloxacin-only treated animals in this model. The levels of dsDNA in middle ear effusion samples are elevated in both humans and mice with CSOM and decreased during treatment, suggesting that dsDNA may serve as a molecular biomarker of treatment response. Together these data strongly implicate neutrophils in the ineffective immune response to P. aeruginosa infection in CSOM and suggest that immunomodulatory strategies may benefit drug-tolerant infections for chronic biofilm-mediated disease.
format	article
author	K. M. Khomtchouk L. I. Joseph B. B. Khomtchouk A. Kouhi S. Massa A. Xia I. Koliesnik D. Pletzer P. L. Bollyky P. L. Santa Maria
author_facet	K. M. Khomtchouk L. I. Joseph B. B. Khomtchouk A. Kouhi S. Massa A. Xia I. Koliesnik D. Pletzer P. L. Bollyky P. L. Santa Maria
author_sort	K. M. Khomtchouk
title	Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media
title_short	Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media
title_full	Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media
title_fullStr	Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media
title_full_unstemmed	Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media
title_sort	treatment with a neutrophil elastase inhibitor and ofloxacin reduces p. aeruginosa burden in a mouse model of chronic suppurative otitis media
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/7b834c89fd354cdaa19d65fb3bc5042d
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Treatment with a neutrophil elastase inhibitor and ofloxacin reduces P. aeruginosa burden in a mouse model of chronic suppurative otitis media

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