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Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology

Respiratory syncytial virus induces indoleamine 2,3-dioxygenase activity: a potential novel role in the development of allergic disease.


PMID 25627660

Abstract

Infants that develop severe bronchiolitis due to respiratory syncytial virus (RSV) are at increased risk of developing asthma later in life. We investigated a potential immunological mechanism for the association between RSV and the development of allergic inflammation. The enzyme indoleamine 2,3-dioxygenase (IDO) has been reported to induce selective apoptosis of T helper 1 (Th1) cells and contributed to Th2-biased immune responses. To determine whether RSV infection in vitro could induce IDO expression and bioactivity in human dendritic cells, leading to a Th2-biased immune response. Human peripheral blood monocytes from healthy adult donors were isolated, differentiated to dendritic cells (moDC), in vitro. We studied RSV infection and mechanisms of IDO activation in moDC with subsequent effect on T-bet expression. We found that moDC were infected by RSV and that this induced IDO activation. RSV-induced IDO activity was inhibited by palivizumab, UV inactivation, TL4R inhibition, and ribavirin. However, blocking endosomal TLR function with chloroquine did not inhibit IDO activity. Selective inhibitors suggested that RSV-induced IDO activity was dependent on the retinoic acid-inducible gene-I (RIG-I) related pathway via NF-κB and p38 MAPK. Coculture of RSV-infected moDC with activated T cells, in a transwell system, suppressed expression of T-bet (a Th1-associated factor) but not GATA3 (a Th2 regulator). Inhibition of IDO activity with the competitive inhibitor, 1-methyl tryptophan, blocked the effect on T-bet expression. Our data show for the first time that RSV can induce the expression and bioactivity of IDO in human moDC, in a virus replication-dependant fashion. We suggest that RSV activation of IDO could be a potential mechanism for the development of allergic diseases.

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