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TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection.
Clin Exp Allergy 2014; 44(1):91-101CE

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.

Authors+Show Affiliations

Centre for Asthma and Respiratory Disease and Hunter Medical Research Institute, The University of Newcastle, New Lambton Heights, NSW, Australia.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24131248

Citation

Parsons, K S., et al. "TLR3 and MDA5 Signalling, Although Not Expression, Is Impaired in Asthmatic Epithelial Cells in Response to Rhinovirus Infection." Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology, vol. 44, no. 1, 2014, pp. 91-101.
Parsons KS, Hsu AC, Wark PA. TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection. Clin Exp Allergy. 2014;44(1):91-101.
Parsons, K. S., Hsu, A. C., & Wark, P. A. (2014). TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection. Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology, 44(1), pp. 91-101. doi:10.1111/cea.12218.
Parsons KS, Hsu AC, Wark PA. TLR3 and MDA5 Signalling, Although Not Expression, Is Impaired in Asthmatic Epithelial Cells in Response to Rhinovirus Infection. Clin Exp Allergy. 2014;44(1):91-101. PubMed PMID: 24131248.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection. AU - Parsons,K S, AU - Hsu,A C, AU - Wark,P A B, PY - 2013/04/17/received PY - 2013/09/26/revised PY - 2013/10/12/accepted PY - 2013/10/18/entrez PY - 2013/10/18/pubmed PY - 2014/8/13/medline KW - MDA-5 KW - TLR-3 KW - asthma KW - innate immune response KW - rhinovirus SP - 91 EP - 101 JF - Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology JO - Clin. Exp. Allergy VL - 44 IS - 1 N2 - 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. SN - 1365-2222 UR - https://www.unboundmedicine.com/medline/citation/24131248/TLR3_and_MDA5_signalling_although_not_expression_is_impaired_in_asthmatic_epithelial_cells_in_response_to_rhinovirus_infection_ L2 - https://doi.org/10.1111/cea.12218 DB - PRIME DP - Unbound Medicine ER -