| Title | Enterovirus D68 infection induces IL-17-dependent neutrophilic airway inflammation and hyperresponsiveness. | ||
| Author | Rajput, Charu; Han, Mingyuan; Bentley, J Kelley; Lei, Jing; Ishikawa, Tomoko; Wu, Qian; Hinde, Joanna L; Callear, Amy P; Stillwell, Terri L; Jackson, William T; Martin, Emily T; Hershenson, Marc B | ||
| Journal | JCI Insight | Publication Year/Month | 2018-Aug |
| PMID | 30135310 | PMCID | PMC6141171 |
| Affiliation + expend | 1.Departments of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA. | ||
Enterovirus D68 (EV-D68) shares biologic features with rhinovirus (RV). In 2014, a nationwide outbreak of EV-D68 was associated with severe asthma-like symptoms. We sought to develop a mouse model of EV-D68 infection and determine the mechanisms underlying airway disease. BALB/c mice were inoculated intranasally with EV-D68 (2014 isolate), RV-A1B, or sham, alone or in combination with anti-IL-17A or house dust mite (HDM) treatment. Like RV-A1B, lung EV-D68 viral RNA peaked 12 hours after infection. EV-D68 induced airway inflammation, expression of cytokines (TNF-alpha, IL-6, IL-12b, IL-17A, CXCL1, CXCL2, CXCL10, and CCL2), and airway hyperresponsiveness, which were suppressed by anti-IL-17A antibody. Neutrophilic inflammation and airway responsiveness were significantly higher after EV-D68 compared with RV-A1B infection. Flow cytometry showed increased lineage-, NKp46-, RORgammat+ IL-17+ILC3s and gammadelta T cells in the lungs of EV-D68-treated mice compared with those in RV-treated mice. EV-D68 infection of HDM-exposed mice induced additive or synergistic increases in BAL neutrophils and eosinophils and expression of IL-17, CCL11, IL-5, and Muc5AC. Finally, patients from the 2014 epidemic period with EV-D68 showed significantly higher nasopharyngeal IL-17 mRNA levels compared with patients with RV-A infection. EV-D68 infection induces IL-17-dependent airway inflammation and hyperresponsiveness, which is greater than that generated by RV-A1B, consistent with the clinical picture of severe asthma-like symptoms.