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      Immunoproteasomes as a novel antiviral mechanism in rhinovirus-infected airways

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          Abstract

          Rhinovirus (RV) infection is involved in acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). RV primarily infects upper and lower airway epithelium. Immunoproteasomes (IP) are proteolytic machineries with multiple functions including the regulation of MHC class I antigen processing during viral infection. However, the role of IP in RV infection has not been explored. We sought to investigate the expression and function of IP during airway RV infection. Primary human tracheobronchial epithelial (HTBE) cells were cultured at air–liquid interface (ALI) and treated with RV16, RV1B, or interferon (IFN)-λ in the absence or presence of an IP inhibitor (ONX-0914). IP gene (i.e. LMP2) deficient mouse tracheal epithelial cells (mTECs) were cultured for the mechanistic studies. LMP2-deficient mouse model was used to define the in vivo role of IP in RV infection. IP subunits LMP2 and LMP7, antiviral genes MX1 and OAS1 and viral load were measured. Both RV16 and RV1B significantly increased the expression of LMP2 and LMP7 mRNA and proteins, and IFN-λ mRNA in HTBE cells. ONX-0914 down-regulated MX1 and OAS1, and increased RV16 load in HTBE cells. LMP2-deficient mTECs showed a significant increase in RV1B load compared with the wild-type (WT) cells. LMP2-deficient (compared with WT) mice increased viral load and neutrophils in bronchoalveolar lavage (BAL) fluid after 24 h of RV1B infection. Mechanistically, IFN-λ induction by RV infection contributed to LMP2 and LMP7 up-regulation in HTBE cells. Our data suggest that IP are induced during airway RV infection, which in turn may serve as an antiviral and anti-inflammatory mechanism.

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          Author and article information

          Journal
          7905731
          3071
          Clin Sci (Lond)
          Clin. Sci.
          Clinical science (London, England : 1979)
          0143-5221
          1470-8736
          18 March 2020
          16 August 2018
          16 August 2018
          31 March 2020
          : 132
          : 15
          : 1711-1723
          Affiliations
          [1 ]Department of Medicine, National Jewish Health, Denver, CO, U.S.A.;
          [2 ]Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, U.S.A.
          Author notes

          Author contribution

          K.G.D. performed most of the experimental work and wrote the manuscript. H.W.C. and D.A.F. supervised the study, designed the experiments, and helped draft the manuscript. A.S., N.S., and J.P. collected in vivo samples and assisted in the experiments, data analysis and presentation. All authors approved the paper for publication.

          Correspondence: Hong Wei Chu ( chuhw@ 123456njhealth.org ) or Deborah A. Ferrington ( ferri013@ 123456umn.edu )
          Article
          PMC7105891 PMC7105891 7105891 nihpa1576557
          10.1042/CS20180337
          7105891
          29980604
          e5f76211-4864-45cd-ae95-0c73a5d43bdd
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