title: Respiratory Syncytial Virus Infection Upregulates NLRC5 and Major Histocompatibility Complex Class I Expression through RIG-I Induction in Airway Epithelial Cells.
abstract: Respiratory syncytial virus (RSV) is the leading cause of acute respiratory tract viral infection in infants, causing bronchiolitis and pneumonia. The host antiviral response to RSV acts via retinoic acid-inducible gene I (RIG-I). We show here that RSV infection upregulates major histocompatibility complex class I (MHC-I) expression through the induction of NLRC5, a NOD-like, CARD domain-containing intracellular protein that has recently been identified as a class I MHC transactivator (CITA). RSV infection of A549 cells promotes upregulation of NLRC5 via beta interferon (IFN-β) production, since the NLRC5-inducing activity in a conditioned medium from RSV-infected A549 cells was removed by antibody to IFN-β, but not by antibody to IFN-γ. RSV infection resulted in RIG-I upregulation and induction of NLRC5 and MHC-I. Suppression of RIG-I induction significantly blocked NLRC5, as well as MHC-I, upregulation and diminished IRF3 activation. Importantly, Vero cells deficient in interferon production still upregulated MHC-I following introduction of the RSV genome by infection or transfection, further supporting a key role for RIG-I. A model is therefore proposed in which the host upregulates MHC-I expression during RSV infection directly via the induction of RIG-I and NLRC5 expression. Since elevated expression of MHC-I molecules can sensitize host cells to T lymphocyte-mediated cytotoxicity or immunopathologic damage, the results have significant implications for the modification of immunity in RSV disease.
  
  
  OBJECTIVE
  Human respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants and young children worldwide. Infection early in life is linked to persistent wheezing and allergic asthma in later life, possibly related to upregulation of major histocompatibility class I (MHC-I) on the cell surface, which facilitates cytotoxic T cell activation and antiviral immunity. Here, we show that RSV infection of lung epithelial cells induces expression of RIG-I, resulting in induction of a class I MHC transactivator, NLRC5, and subsequent upregulation of MHC-I. Suppression of RIG-I induction blocked RSV-induced NLRC5 expression and MHC-I upregulation. Increased MHC-I expression may exacerbate the RSV disease condition due to immunopathologic damage, linking the innate immune response to RSV disease.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and School of Medicine, Nanjing University, Nanjing, Jiangsu, China Jiangsu Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Xuancheng
authors.initials: X
authors.lastname: Guo
authors.affiliation: Jiangsu Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China Jiangsu Province Blood Center, Nanjing, Jiangsu, China.
authors.forename: Taixiang
authors.initials: T
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and School of Medicine, Nanjing University, Nanjing, Jiangsu, China Jiangsu Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Hengfei
authors.initials: H
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and School of Medicine, Nanjing University, Nanjing, Jiangsu, China College of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and School of Medicine, Nanjing University, Nanjing, Jiangsu, China Jiangsu Province Blood Center, Nanjing, Jiangsu, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ji
authors.affiliation: Jiangsu Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and School of Medicine, Nanjing University, Nanjing, Jiangsu, China Jiangsu Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and School of Medicine, Nanjing University, Nanjing, Jiangsu, China College of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.
authors.forename: Ren Xiang
authors.initials: RX
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and School of Medicine, Nanjing University, Nanjing, Jiangsu, China Jiangsu Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China erguang@nju.edu.cn.
authors.forename: Erguang
authors.identifier: http://orcid.org/0000-0002-3065-1336
authors.initials: E
authors.lastname: Li
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000821:virology; D015234:HLA-A Antigens / Q000235:genetics* / Q000378:metabolism; D015235:HLA-B Antigens / Q000235:genetics* / Q000378:metabolism; D015236:HLA-C Antigens / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000821:virology; D011971:Receptors, Immunologic; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics* / Q000378:metabolism / Q000821:virology; D018113:Respiratory Syncytial Virus, Human / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D014709:Vero Cells
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D015236:HLA-C Antigens; D047908:Intracellular Signaling Peptides and Proteins; C548042:NLRC5 protein, human; D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases