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Enterovirus D68 infection induces IL-17–dependent neutrophilic airway inflammation and hyperresponsiveness
Charu Rajput, … , Emily T. Martin, Marc B. Hershenson
Charu Rajput, … , Emily T. Martin, Marc B. Hershenson
Published August 23, 2018
Citation Information: JCI Insight. 2018;3(16):e121882. https://doi.org/10.1172/jci.insight.121882.
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Research Article Infectious disease Pulmonology

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

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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.

Authors

Charu Rajput, Mingyuan Han, J. Kelley Bentley, Jing Lei, Tomoko Ishikawa, Qian Wu, Joanna L. Hinde, Amy P. Callear, Terri L. Stillwell, William T. Jackson, Emily T. Martin, Marc B. Hershenson

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Figure 3

EV-D68 induces greater neutrophil inflammation than RV-A1B.

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EV-D68 induces greater neutrophil inflammation than RV-A1B.
Female 8- to...
Female 8- to 10-week-old BALB/c mice were treated with sham, 5 × 106 ePFU of EV-D68, or 5 × 106 PFU of RV-A1B. Mice were sacrificed 48 hours later and analyzed for histology, BAL, and qPCR. In another set of mice, changes in airway resistance to nebulized increasing doses of methacholine (0 to 40mg/ml) were assessed. (A) Images showing the inflammation in lungs 48 hours after treatment with sham, EV-D68, or RV-A1B. Images were taken at ×200 magnification. (B) Analysis of BAL inflammatory cells. (C) qPCR analysis of indicated genes. (D) BAL IL-17 protein levels in the indicated groups. (E) Airway responsiveness to methacholine in the 3 groups of mice. Data are shown as mean ± SEM of 3–5 mice/group from at least 2 different experiments; *P < 0.05 by 1-way ANOVA, compared with sham; †P < 0.05 by 1-way ANOVA, compared with RV-1B.

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