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

JCI Insight. 2018 Aug 23;3(16):e121882. doi: 10.1172/jci.insight.121882.

Abstract

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.

Keywords: Allergy; Asthma; Cytokines; Infectious disease; Pulmonology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Allergens
  • IL17A protein, human
  • Il17a protein, mouse
  • Interleukin-17
  • RNA, Messenger

Supplementary concepts

  • Rhinovirus A