TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection

Clin Exp Allergy. 2014 Jan;44(1):91-101. doi: 10.1111/cea.12218.

Abstract

Background: Rhinoviruses (RV) are the most common acute triggers of asthma, and airway epithelial cells are the primary site of infection. Asthmatic bronchial epithelial cells (BECs) have been found to have impaired innate immune responses to RV. RV entry and replication is recognized by pathogen recognition receptors (PRRs), specifically toll-like receptor (TLR)3 and the RNA helicases; retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5).

Objective: Our aim was to assess the relative importance of these PRRs in primary bronchial epithelial cells (pBEC) from healthy controls and asthmatics following RV infection and determine whether deficient innate immune responses in asthmatic pBECs were due to abnormal signalling via these PRRs.

Methods: The expression patterns and roles of TLR3 and MDA5 were investigated using siRNA knock-down, with subsequent RV1B infection in pBECs from each patient group. We also used BX795, a specific inhibitor of TBK1 and IKKi.

Results: Asthmatic pBECs had significantly reduced release of IL-6, CXCL-8 and IFN-λ in response to RV1B infection compared with healthy pBECs. In healthy pBECs, siMDA5, siTLR3 and BX795 all reduced release of IL-6, CXCL-10 and IFN-λ to infection. In contrast, in asthmatic pBECs where responses were already reduced, there was no further reduction in IL-6 and IFN-λ, although there was in CXCL-10.

Conclusion and clinical relevance: Impaired antiviral responses in asthmatic pBECs are not due to deficient expression of PRRs; MDA5 and TLR3, but an inability to later activate types I and III interferon immune responses to RV infection, potentially increasing susceptibility to the effects of RV infection.

Keywords: MDA-5; TLR-3; asthma; innate immune response; rhinovirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Asthma / genetics*
  • Asthma / immunology
  • Asthma / metabolism*
  • Asthma / virology
  • Case-Control Studies
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / genetics*
  • DEAD-box RNA Helicases / metabolism*
  • Epithelial Cells / metabolism
  • Epithelial Cells / virology
  • Female
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Interferon Regulatory Factor-3 / antagonists & inhibitors
  • Interferon-Induced Helicase, IFIH1
  • Interferons / biosynthesis
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism
  • Male
  • Middle Aged
  • Picornaviridae Infections / genetics
  • Picornaviridae Infections / immunology
  • Picornaviridae Infections / metabolism
  • Receptors, Immunologic
  • Respiratory Mucosa / immunology
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / virology
  • Rhinovirus / immunology
  • Signal Transduction*
  • Toll-Like Receptor 3 / genetics*
  • Toll-Like Receptor 3 / metabolism*

Substances

  • Interferon Regulatory Factor-3
  • Interleukin-6
  • Interleukin-8
  • Receptors, Immunologic
  • Toll-Like Receptor 3
  • Interferons
  • DDX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1