期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 203, 期 9, 页码 1099-1111出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.202005-1596OC
关键词
microbiome; inflammation; transcriptomics; pathogen susceptibility
资金
- Stony Wold Herbert Foundation
- NIH/National Cancer Institute (NCI) [5 P30CA16087, S10 OD021747]
- AbbVie Inc.
- Amgen Inc.
- Boehringer-Ingelheim Pharma GmbH Co. KG
- Bristol-Myers Squibb
- Celgene Corporation
- Genentech Inc.
- Gilead
- GlaxoSmithKline plc
- Janssen Pharmaceutical Companies of Johnson Johnson
- Novartis Institutes for Biomedical Research
- Pfizer Inc.
- Sanofi
- NIH/NHLBI [R01 HL125816]
- PACT grant (Foundation of the NIH)
- New York University Genome Technology Center
- Flight Attendant Medical Research Institute Young Clinical Scientist Award
- NIH/NCI [R37 CA244775]
- Stony Wold Herbert Foundation grant-in-aid
- [T32 CA193111]
- [UL1TR001445]
- [L30 AI138249]
- [K23 AI102970]
The study found that aspiration with oral commensals in mice led to short-term lower-airway dysbiosis, but induced a prolonged inflammatory response, including IL-17-producing T cells, lasting at least 14 days. Furthermore, aspiration with oral commensals decreased hosts' susceptibility to respiratory challenge with S. pneumoniae.
Rationale: Cross-sectional human data suggest that enrichment of oral anaerobic bacteria in the lung is associated with an increased T-helper cell type 17 (Th17) inflammatory phenotype. Objectives: In this study, we evaluated the microbial and host immune-response dynamics after aspiration with oral commensals using a preclinical mouse model. Methods: Aspiration with a mixture of human oral commensals (MOC; Prevotella melaninogenica, Veillonella parvula, and Streptococcus mitis) was modeled in mice followed by variable time of killing. The genetic backgrounds of mice included wild-type, MyD88-knockout, and STAT3C backgrounds. Measurements and Main Results: 16S-rRNA gene sequencing characterized changes in microbiota. Flow cytometry, cytokine measurement via Luminex and RNA host-transcriptome sequencing was used to characterize the host immune phenotype. Although MOC aspiration correlated with lower-airway dysbiosis that resolved within 5 days, it induced an extended inflammatory response associated with IL-17-producing T cells lasting at least 14 days. MyD88 expression was required for the IL-17 response to MOC aspiration, but not for T-cell activation or IFN-gamma expression. MOC aspiration before a respiratory challenge with S. pneumoniae led to a decrease in hosts' susceptibility to this pathogen. Conclusions: Thus, in otherwise healthy mice, a single aspiration event with oral commensals is rapidly cleared from the lower airways but induces a prolonged Th17 response that secondarily decreases susceptibility to S. pneumoniae. Translationally, these data implicate an immunoprotective role of episodic microaspiration of oral microbes in the regulation of the lung immune phenotype and mitigation of host susceptibility to infection with lower-airway pathogens.
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