Aeroallergen-induced IL-33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity Jason P. Lynch, PhD, Rhiannon B. Werder, B.

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Aeroallergen-induced IL-33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity Jason P. Lynch, PhD, Rhiannon B. Werder, B Biomed Sci (Hons), Jennifer Simpson, B Biomed Sci (Hons), Zhixuan Loh, B Biomed Sci (Hons), Vivian Zhang, PhD, Ashraful Haque, PhD, Kirsten Spann, PhD, Peter D. Sly, MD, PhD, Stuart B. Mazzone, PhD, John W. Upham, MD, PhD, Simon Phipps, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 5, Pages 1326-1337 (November 2016) DOI: 10.1016/j.jaci.2016.02.039 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Pneumovirus and allergen coexposure synergize in both early and later life to promote type 2 inflammation and airway remodeling. A, Study design. B, Peribronchial eosinophils expressed per 100 μm of the epithelial basement membrane (BM). C, Mucus-secreting cells as a percentage of AECs. D, Serum levels of cockroach-specific IgG1a measured by ELISA. E, Top panel, Peribronchial collagen area; bottom panel, representative micrograph (×400 magnification). Scale bar = 50 μm. White arrow indicates collagen (blue). F, Top panel, Peribronchial periostin; bottom panel, representative micrograph (×1000 magnification). Scale bar = 10 μm. White arrow indicates periostin (pink). G, Top panel, Peribronchial ASM area; bottom panel, representative micrographs of ASM (×400 magnification). Scale bar = 50 μm. White arrow indicates ASM (pink). BM, Basement membrane. Data are means ± SEMs and representative of 3 independent experiments (n = 6-9 mice per group). *P < .05, **P < .01, and ***P < .001 compared with vehicle-treated mice. #P < .05, ##P < .01, and ###P < .001 compared with PVM/CRE/PVM/CRE mice. Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Early-life CRE exposure increases viral load and dampens antiviral cytokine production. A, Viral load in AECs detected by using immunohistochemistry and enumerated as a percentage of total AECs. B, Edema in lung parenchyma. C, Weight gain. D, IFN-α, IFN-λ, and IFN-γ levels in BALF and IL-12p40 levels in lung homogenate. E, mRNA expression of interferon-regulatory factor 7 (IRF7), viperin, and signal transducer and activator of transcription 1 (STAT1) in lungs relative to those in vehicle-treated mice. Data are means ± SEMs and representative of 2 to 3 experiments (n = 4-6 mice per group). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001 compared with vehicle-treated mice. #P < .05, ##P < .01, and ###P < .001 compared with PVM/CRE mice. Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Type 2 inflammation in early life is increased in PVM/CRE-coexposed mice. A and B, IL-33 in lung homogenate (Fig 3, A) and BALF (Fig 3, B). C, Representative micrographs of IL-33 immunostaining plus 4′,6-diamidino-2-phenylindole (DAPI) counterstaining. Scale bar = 50 μm. D, Type 2 ILCs in lung (Lineage−CD45+CD90.2+CD25+ST2+). E, Peribronchial eosinophils. F, IL-5 and IL-13 in BALF. G, ASM area. BM, Basement membrane. Data are means ± SEMs and representative of 2 independent experiments (n = 6-8 mice per group). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001 compared with vehicle-treated mice. #P < .05, ##P < .01, and ###P < .001 compared with PVM/CRE mice. Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 High viral load alone does not promote type 2 inflammation and airway remodeling. A and E, Viral load in AECs. B, Survival curve after intranasal infection with 1 or 10 pfu of PVM. C and G, IL-33 in BALF. D and F, ASM area. H, IFN-α, IFN-λ, and IFN-γ levels in BALF and IL-12p40 levels in lung homogenate. I, Type 2 ILCs in lung. BM, Basement membrane. Data are means ± SEMs and representative of 2 independent experiments (n = 6-8 mice per group). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001 compared with PVM-treated mice. #P < .05, ##P < .01, and ###P < .001 compared with PVM/CRE mice. Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Anti–IL-33 prevents type 2 inflammation and remodeling in response to PVM and CRE coexposure in early life. A, Type 2 ILCs in lung. B, IL-13 in BALF. C, Peribronchial eosinophils. D, ASM area. Data are means ± SEMs and representative of 2 experiments (n = 6-7 mice per group). BM, Basement membrane. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001 compared with isotype-treated PVM/CRE-coexposed mice. Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 IL-33 blockade in PVM/CRE-coexposed mice prevents excessive viral load and reverses dampened antiviral immunity induced by CRE. A and D, AEC viral load. B and E, IFN-α and IFN-λ levels in BALF and IL-12p40 levels in lung homogenate. C and F, mRNA expression of ISGs relative to vehicle-treated mice. G, ASM area. H, Type 2 ILCs were treated with IL-2 with or without IFN-α for 30 minutes, followed by culture with IL-33 and IL-2 for 72 hours, before the supernatant was probed for IL-5 and IL-13. I, ST2 expression on cultured type 2 ILCs. MFI, Mean fluorescence intensity. Data are means ± SEMs and representative of 2 to 3 independent experiments (n = 6-10 mice per group). BM, Basement membrane. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001 compared with PVM/CRE/isotype mice or as indicated. Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Exogenous IL-33 dampens IFN-α production and increases viral load by decreasing IRAK1 expression and antiviral cytokine production by pDCs. A and B, IFN-α (Fig 7, A) and IFN-λ (Fig 7, B) in BALF. C, Viral load in AECs. D, mRNA expression relative to vehicle-treated mice. E, ASM area. F, ST2 staining of bone marrow (BM), lung, and mediastinal lymph node (LN) pDCs (solid line). Fluorescence minus one for ST2 staining is shown in gray. G, IRAK1 and viperin intracellular expression in pDC in vivo at 2 hours after CRE administration. MFI, Mean fluorescence intensity. H, Intracellular IRAK1 staining of bone marrow–derived pDCs preincubated with vehicle (solid line) or IL-33 (3 ng/mL, dotted line) for 0.5 hours. Fluorescence minus one for IRAK staining is shown in gray. I, IFN-α production in bone marrow–derived pDC cell-culture supernatants. BM, Basement membrane. Data are means ± SEMs and representative of 2 independent experiments (n = 7 mice per group). n.d., Not detected. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001 compared with mice exposed to PVM alone or vehicle-treated bone marrow–derived pDCs. Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Journal of Allergy and Clinical Immunology 2016 138, 1326-1337DOI: (10.1016/j.jaci.2016.02.039) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions