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

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 f...

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Bibliographic Details
Published in:NPJ biofilms and microbiomes 2021-04, Vol.7 (1), p.31-31, Article 31
Main Authors: Khomtchouk, K. M., Joseph, L. I., Khomtchouk, B. B., Kouhi, A., Massa, S., Xia, A., Koliesnik, I., Pletzer, D., Bollyky, P. L., Santa Maria, P. L.
Format: Article
Language:English
Subjects:
631/326/22
631/326/41
631/326/421
631/326/46
Antibiotics
Biofilms
Biomedical and Life Sciences
Ear diseases
Effusion
Elastase
Flow cytometry
Immune response
Immunomodulation
Infections
Learning algorithms
Leukocytes (neutrophilic)
Life Sciences
Machine learning
Medical Microbiology
Microbial Ecology
Microbial Genetics and Genomics
Microbiology
Middle ear
Neutrophils
Ofloxacin
Otitis media
Pseudomonas aeruginosa
Surface markers
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Summary: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.
ISSN:2055-5008
2055-5008
DOI:10.1038/s41522-021-00200-z