Mechanisms of allergy and clinical immunology
Thymic stromal lymphopoietin is induced by respiratory syncytial virus–infected airway epithelial cells and promotes a type 2 response to infection

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Background

Respiratory viral infection, including respiratory syncytial virus (RSV) and rhinovirus, has been linked to respiratory disease in pediatric patients, including severe acute bronchiolitis and asthma exacerbation.

Objective

The study examined the role of the epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) in the response to RSV infection.

Methods

Infection of human airway epithelial cells was used to examine TSLP induction after RSV infection. Air–liquid interface cultures from healthy children and children with asthma were also tested for TSLP production after infection. Finally, a mouse model was used to directly test the role of TSLP signaling in the response to RSV infection.

Results

Infection of airway epithelial cells with RSV led to the production of TSLP via activation of an innate signaling pathway that involved retinoic acid induced gene I, interferon promoter-stimulating factor 1, and nuclear factor-κB. Consistent with this observation, airway epithelial cells from asthmatic children a produced significantly greater levels of TSLP after RSV infection than cells from healthy children. In mouse models, RSV-induced TSLP expression was found to be critical for the development of immunopathology.

Conclusion

These findings suggest that RSV can use an innate antiviral signaling pathway to drive a potentially nonproductive immune response and has important implications for the role of TSLP in viral immune responses in general.

Section snippets

Cells and virus

Normal human BECs (NHBECs) were maintained in appropriate medium according to the manufacturer's instruction (Lonza, Walkersville, Md). The human lung epithelial cell line A549 was maintained in Dulbecco modified Eagle medium (DMEM) with 10% FBS and antibiotics. Murine air-liquid interface (ALI) cultures were grown from mouse tracheal epithelial cells and differentiated as described.13 Generation of RIG-I knockout (KO) and IFN-α receptor KO mouse embryonic fibroblasts (MEFs) was previously

Induction of human TSLP expression by RSV infection of primary AECs

Severe infection with the family Paramyxoviridae virus during childhood was found to strongly correlate with subsequent asthma development, and infection in adults with asthma commonly led to significant bouts of exacerbated disease. Further, a significant body of work has now reported the critical nature of TSLP expression by AECs in promoting the asthma phenotype.5, 7 In addition, several studies have now reported that infection of AECs with a variety of viruses or treatment with the viral

Discussion

The important role of respiratory virus infection on the onset of asthma, as well as the exacerbation of disease in patients with established asthma, has become clear.36, 37, 38 However, the mechanism responsible for these effects has remained unclear. In this study, we report that infection of airway epithelium with Paramyxoviridae family viruses induces robust expression of TSLP, a TH2-promoting cytokine. This finding is particularly interesting given that RSV infection in young children has

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    Supported by the National Institutes of Health (grants AI068731, HL098067, AR055695, and AR056113 to S.F.Z.; grant HL102708 to S.F.Z. and J.S.D.; grants AI060389 and AI083019 to M.G. Jr; and grant HL059178 to N.W.L.).

    Disclosure of potential conflict of interest: M. Headley, M. Gale, J. S. Debley, and N. W. Lukacs have received research support from the National Institutes of Health (NIH). S. F. Ziegler has received research support from the NIH, has received lecture fees from the American Academy of Allergy, Asthma & Immunology, and has received travel expenses from the Federation of Clinical Immunology Services. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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