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Allergen Inflammation After Prior Exposure to House Dust Mite Rhinovirus Infection Promotes Eosinophilic Airway Inflammation after Prior Exposure to House Dust Mite Allergen Downloaded from Amit K. Mehta and Michael Croft ImmunoHorizons 2020, 4 (8) 498-507 doi: https://doi.org/10.4049/immunohorizons.2000052 http://www.immunohorizons.org/content/4/8/498 http://www.immunohorizons.org/ This information is current as of September 26, 2021. Supplementary http://www.immunohorizons.org/content/suppl/2020/08/13/4.8.498.DCSupp Material lemental References This article cites 35 articles, 12 of which you can access for free at: http://www.immunohorizons.org/content/4/8/498.full#ref-list-1 by guest on September 26, 2021 Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://www.immunohorizons.org/alerts ImmunoHorizons is an open access journal published by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. ISSN 2573-7732. RESEARCH ARTICLE Infectious Disease Rhinovirus Infection Promotes Eosinophilic Airway Inflammation after Prior Exposure to House Dust Mite Allergen Amit K. Mehta,*,1 and Michael Croft*† *Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology, La Jolla, CA 92037; and †Department of Medicine, University of California, San Diego, La Jolla, CA 92093 Downloaded from ABSTRACT Respiratory virus infection normally drives neutrophil-dominated airway inflammation, yet some viral infections result in an http://www.immunohorizons.org/ eosinophil-dominated response in individuals such as allergic asthmatics. One idea is that viral infection simply exacerbates an ongoing type 2 response to allergen. However, prior exposure to allergen might alter the virus-induced innate response such that type 2–like eosinophilic inflammation can be induced. To test this, mice were sensitized intranasally with house dust mite allergen and then at later times exposed to rhinovirus RV1B via the airways. RV1B infection of naive mice led to the expected neutrophilic lung inflammatory response with no eosinophils or mucus production. In contrast, if mice were exposed to RV1B 1–4 wk after house dust mite inhalation, when the allergen response had subsided, infection led to eosinophilia and mucus production and a much stronger lymphocyte response that were partially or fully steroid resistant. In accordance, RV1B infection resulted in elevated expression of several inflammatory factors in allergen–pre-exposed mice, specifically those associated with type 2 immunity, namely CCL17, CXCL1, CCL2, IL-33, and IL-13. In vitro studies further showed that RV infection led to greater production of chemokines and cytokines in human bronchial epithelial cells that were previously stimulated with allergen, reinforcing the notion of an altered virus by guest on September 26, 2021 response after allergen exposure. In conclusion, we report that prior allergen exposure can modify responsiveness of cells in the lungs such that a qualitatively and quantitatively different inflammatory activity results following virus infection that is biased toward type 2–like airway disease. ImmunoHorizons, 2020, 4: 498–507. INTRODUCTION Cold viruses might drive this type of response, including rhinovirus (RV) (1–5). Typical of most viruses, RVs largely result There is considerable interest in the inflammatory response to in a neutrophil-dominated innate inflammatory response post- viruses that infect the respiratory tract. Most viruses are thought infection, with little or no signs of type 2 immunity, such as mucus to drive a type 1/17–like immune response, resulting in lung production or infiltration of eosinophils into the lungs. Thus, what neutrophilia; however, a number of viral respiratory tract dictates the induction of a neutrophilic versus eosinophilic infections have been linked to type 2–like inflammation typical response is not clear. A number of studies have tried to address of asthma. It has been suggested that viral infections may cause up this in mouse models with coexposure to RV and allergen at the to 90% of asthma-like symptoms in children and 60% in adults. same time. In some studies, with house dust mite (HDM) allergen, Received for publication June 16, 2020. Accepted for publication July 28, 2020. Address correspondence and reprint requests to: Prof. Michael Croft, Division of Immune Regulation, La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: mick@lji.org ORCID: 0000-0002-6062-3635 (M.C.). 1Current address: Fate Therapeutics, La Jolla, CA. This work was supported by National Institutes of Health Grant AI070535 (to M.C.). A.K.M. performed experiments. M.C. and A.K.M. wrote the manuscript. Abbreviations used in this article: BAL, bronchoalveolar lavage; DC, dendritic cell; HDM, house dust mite; i.n., intranasal, intranasally; PAS, periodic acid–Schiff; RV, rhinovirus. The online version of this article contains supplemental material. This article is distributed under the terms of the CC BY-NC-ND 4.0 Unported license. Copyright © 2020 The Authors 498 https://doi.org/10.4049/immunohorizons.2000052 ImmunoHorizons is published by The American Association of Immunologists, Inc. ImmunoHorizons RHINOVIRUS INDUCES ALLERGIC LUNG INFLAMMATION 499 the investigators failed to demonstrate enhancement of type 2 Institute for Immunology Animal Care Committee in accordance inflammation upon concomitant airway exposure to RV; however, with guidelines of the Association for the Assessment and they did find an increased neutrophil response characteristic of Accreditation of Laboratory Animal Care. that which can be induced by RV infection alone (6–8). Alternatively, other studies found that RV infection given at the RV generation and experimental protocols same time as the model allergen OVA or HDM, or 1 d later, led to RV1B stocks were generated as described elsewhere (16). For enhanced lung infiltration of eosinophils, augmented mucus allergen experiments, mice were sensitized intranasally (i.n.) with production, and an overall greater type 2 response than driven 50 mg of HDM extract (Greer Labs, Lenoir, NC) given on days 0, 1, by the allergen alone (9–14). The disparity between these results is 7, and 8 and then challenged acutely with 25 mg of HDM given on not clear but could be due to the dose of allergen and strength of days 21, 22, and 23. Twelve or fourteen days or 4 wk later, mice response to the allergen, the content of LPS in the allergen that, were either exposed to PBS or infected with 50 mlofRV1B(;5 3 normally, at high levels promotes type 1/17 immunity or the 107 PFU/ml) given i.n. Mice were sacrificed 24 h after the infection amount of virus used. Regardless, in either case, the data implied for all analyses. For studies with steroid treatment, mice were that infection acted through amplifying the production of type 1/17 sensitized and challenged with HDM as above and either received or type 2 inflammatory mediators in the lungs induced by the PBS or dexamethasone (Sigma-Aldrich) i.n. at 0.5 mg/kg of body Downloaded from allergen. weight in a volume of 50 ml, 30–60 min before the RV1B challenge. An alternative mechanism is also possible to explain a link For some experiments, RV1B was inactivated by exposure to UV between type 2 lung inflammation and virus infection, although at light for 20 min immediately before infection. In other experi- present underexplored. In this scenario, prior allergen exposure ments, mice were sensitized and challenged with HDM as above, could transiently or permanently alter the infectivity of lung with coexposure to PBS or RV1B given i.n. on the same day as the http://www.immunohorizons.org/ epithelialcellsorotherlungcellsbythevirusorcouldaltertheir last challenge with HDM. responsiveness to viral danger signals such that the virus infection alone triggers a response that resembles that normally induced by Bronchoalveolar lavage analysis and lung histology allergen. Along these lines, one publication found that mice that Bronchoalveolar lavage (BAL) was performed 24 h after the RV1B were repeatedly challenged with pneumonia virus and cockroach challenge. BAL fluid was examined for cellular content. BAL cells allergen subsequently displayed both lung eosinophilia and were counted, and BAL cell differentials were determined using neutrophilia and epithelial cell mucus secretion when infected flow cytometry based on cell surface markers. BAL cells were with RV 1 mo later (15). In this study, we present experimental preincubated with mouse Fc-blocking Ab (2.4G2) and then stained evidence in the mouse that supports these data and furthers the with fluorochrome-conjugated Abs (all from BD Biosciences, La idea that prior allergen exposure can modify the airway response Jolla, CA) to Siglec F (PE), Ly-6C (FITC), Gr-1 (APC), CD11b (PE- by guest on September 26, 2021 to virus. Whereas RV infection of naive mice resulted in airway Cy7), CD11c (eFluor 450), and CD45 (PerCp-Cy5.5) for 20 min at neutrophilia without significant eosinophilia or mucus production, 4°C.SampleswereanalyzedonanLSRIIflow cytometer and infection of mice .1wkandupto4wkaftertheywereexposedto FlowJo software. Part of the lung tissue was kept in RNAlater HDM allergen resulted in strong eosinophilia and mucus pro- solution (Invitrogen, San Diego, CA) for RNA isolation. For lung duction together with neutrophilia and an overall larger lung histology, 5–6-mm sections were cut and stained with H&E for inflammatory response. These data correlated with greater examining cell infiltration and
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