Episodic Aspiration with Oral Commensals Induces a MyD88-dependent, Pulmonary T-Helper Cell Type 17 Response that Mitigates Susceptibility to Streptococcus pneumoniae

• Published in: American journal of respiratory and critical care medicine Vol. 203; no. 9; pp. 1099 - 1111
• Main Authors: Wu, Benjamin G, Sulaiman, Imran, Tsay, Jun-Chieh J, Perez, Luisanny, Franca, Brendan, Li, Yonghua, Wang, Jing, Gonzalez, Amber N, El-Ashmawy, Mariam, Carpenito, Joseph, Olsen, Evan, Sauthoff, Maya, Yie, Kevin, Liu, Xiuxiu, Shen, Nan, Clemente, Jose C, Kapoor, Bianca, Zangari, Tonia, Mezzano, Valeria, Loomis, Cynthia, Weiden, Michael D, Koralov, Sergei B, D'Armiento, Jeanine, Ahuja, Sunil K, Wu, Xue-Ru, Weiser, Jeffrey N, Segal, Leopoldo N
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.05.2021
• Subjects: Animals; Disease Models, Animal; Female; Humans; Immune system; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88 - physiology; Original; Pathogens; Pneumococcal Infections - etiology; Pneumococcal Infections - prevention & control; Pneumonia; Prevotella melaninogenica; Pulmonary aspiration; Streptococcus infections; Streptococcus mitis; Streptococcus pneumoniae; Th17 Cells - physiology; Veillonella; transcriptomics; pathogen susceptibility; inflammation; microbiome
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.202005-1596OC

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. In this study, we evaluated the microbial and host immune-response dynamics after aspiration with oral commensals using a preclinical mouse model. Aspiration with a mixture of human oral commensals (MOC; , , and ) was modeled in mice followed by variable time of killing. The genetic backgrounds of mice included wild-type, MyD88-knockout, and STAT3C backgrounds. 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-γ expression. MOC aspiration before a respiratory challenge with led to a decrease in hosts' susceptibility to this pathogen. 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 . 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.