Episodic aspiration with oral commensals induces a MyD88-dependent, pulmonary T-helper cell type 17 response that mitigates susceptibility to streptococcus pneumoniae

Benjamin G. Wu, Imran Sulaiman, Jun Chieh J. Tsay, Luisanny Perez, Brendan Franca, Yonghua Li, Jing Wang, Amber N. Gonzalez, Mariam El-Ashmawy, Joseph Carpenito, Evan Olsen, Maya Sauthoff, Kevin Yie, Xiuxiu Liu, Nan Shen, Jose C. Clemente, Bianca Kapoor, Tonia Zangari, Valeria Mezzano, Cynthia LoomisMichael D. Weiden, Sergei B. Koralov, Jeanine D’Armiento, Sunil K. Ahuja, Xue Ru Wu, Jeffrey N. Weiser, Leopoldo N. Segal

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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’ 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.

Original languageEnglish (US)
Pages (from-to)1099-1111
Number of pages13
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume203
Issue number9
DOIs
StatePublished - May 1 2021

Keywords

  • Inflammation
  • Microbiome
  • Pathogen susceptibility
  • Transcriptomics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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