@article{e094e5b16f20420cbc0dd5a20a2bae03,
title = "Episodic aspiration with oral commensals induces a MyD88-dependent, pulmonary T-helper cell type 17 response that mitigates susceptibility to streptococcus pneumoniae",
abstract = "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-g expression. MOC aspiration before a respiratory challenge with S. pneumoniae led to a decrease in hosts{\textquoteright} 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.",
keywords = "Inflammation, Microbiome, Pathogen susceptibility, Transcriptomics",
author = "Wu, {Benjamin G.} and Imran Sulaiman and Tsay, {Jun Chieh J.} and Luisanny Perez and Brendan Franca and Yonghua Li and Jing Wang and Gonzalez, {Amber N.} and Mariam El-Ashmawy and Joseph Carpenito and Evan Olsen and Maya Sauthoff and Kevin Yie and Xiuxiu Liu and Nan Shen and Clemente, {Jose C.} and Bianca Kapoor and Tonia Zangari and Valeria Mezzano and Cynthia Loomis and Weiden, {Michael D.} and Koralov, {Sergei B.} and Jeanine D{\textquoteright}Armiento and Ahuja, {Sunil K.} and Wu, {Xue Ru} and Weiser, {Jeffrey N.} and Segal, {Leopoldo N.}",
note = "Funding Information: Supported by K23 AI102970 (L.N.S.), a Flight Attendant Medical Research Institute Young Clinical Scientist Award (B.G.W.), a Stony Wold Herbert Foundation grant-in-aid (B.G.W.), T32 CA193111 (B.G.W.), and UL1TR001445 (B.G.W.). Funding for the experimental pathology core laboratory is provided by NIH/National Cancer Institute (NCI) 5 P30CA16087 (V.M. and C.L.) and S10 OD021747 (PerkinElmer/Akoya Biosciences Vectra multispectral imaging system) (V.M. and C.L.). Financial support for the Partnership for Access to Clinical Trials (PACT) project is made possible through funding support provided to the Foundation of the NIH by 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., and Sanofi. Research-support funding was provided by R01 HL125816 (NIH/NHLBI), R37 CA244775 (NIH/NCI), a PACT grant (Foundation of the NIH), the New York University Genome Technology Center, a Flight Attendant Medical Research Institute Young Clinical Scientist Award (B.G.W.), a Stony Wold Herbert Foundation grant-in-aid (B.G.W.), T32 CA193111 (B.G.W.), UL1TR001445 (B.G.W.), and L30 AI138249. Publisher Copyright: Copyright {\textcopyright} 2021 by the American Thoracic Society.",
year = "2021",
month = may,
day = "1",
doi = "10.1164/rccm.202005-1596OC",
language = "English (US)",
volume = "203",
pages = "1099--1111",
journal = "American Review of Respiratory Disease",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "9",
}