Enterovirus D68 infection induces IL-17-dependent neutrophilic airway inflammation and hyperresponsiveness

• Published in: JCI insight Vol. 3; no. 16
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 23.08.2018
• Subjects: Allergens - administration & dosage; Allergens - immunology; Animals; Asthma - immunology; Asthma - pathology; Asthma - virology; Bronchoalveolar Lavage Fluid - cytology; Bronchoalveolar Lavage Fluid - immunology; Cell Line, Tumor; Child; Child, Preschool; Disease Models, Animal; Enterovirus - immunology; Enterovirus - isolation & purification; Enterovirus D, Human - immunology; Enterovirus D, Human - isolation & purification; Enterovirus Infections - immunology; Enterovirus Infections - pathology; Enterovirus Infections - virology; Female; Humans; Infant; Infant, Newborn; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - genetics; Interleukin-17 - immunology; Interleukin-17 - metabolism; Lung - cytology; Lung - pathology; Male; Mice; Nasopharynx - immunology; Nasopharynx - pathology; Nasopharynx - virology; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - metabolism; Pyroglyphidae - immunology; RNA, Messenger - metabolism; Pulmonology; Allergy; Infectious disease; Cytokines; Asthma
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.121882

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-α, 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-, RORγt+ IL-17+ILC3s and γδ 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.