Pulmonary Research Group, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Clin Exp Allergy. 2015 Mar;45(3):644-59. doi: 10.1111/cea.12498.
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.
因呼吸道合胞病毒（RSV）而发生严重细支气管炎的婴儿，日后罹患哮喘的风险增加。我们研究了 RSV 与过敏性炎症发展之间关联的潜在免疫学机制。已报道吲哚胺 2,3-双加氧酶（IDO）可诱导辅助性 T 细胞 1（Th1）细胞的选择性凋亡，并促成 Th2 偏向性免疫反应。
确定 RSV 在体外感染是否可诱导人树突状细胞（moDC）中 IDO 的表达和活性，从而导致 Th2 偏向性免疫反应。
从健康成年供体中分离外周血单核细胞，体外分化为树突状细胞（moDC）。我们研究了 moDC 中的 RSV 感染和 IDO 激活机制，以及对 T 盒转录因子表达的后续影响。
我们发现 moDC 可被 RSV 感染，且 RSV 可诱导 IDO 激活。用帕利珠单抗、UV 失活、TL4R 抑制和利巴韦林可抑制 RSV 诱导的 IDO 活性。然而，用氯喹阻断内体 TLR 功能并不能抑制 IDO 活性。选择性抑制剂提示 RSV 诱导的 IDO 活性依赖于视黄酸诱导基因-I（RIG-I）相关途径，通过 NF-κB 和 p38 MAPK。在 Transwell 系统中，用 RSV 感染的 moDC 与激活的 T 细胞共培养，可抑制 T 盒转录因子（Th1 相关因子）的表达，但不抑制 GATA3（Th2 调节因子）的表达。用竞争性抑制剂 1-甲基色氨酸抑制 IDO 活性，可阻断对 T 盒转录因子表达的影响。
我们的数据首次表明，RSV 可依赖病毒复制诱导人 moDC 中 IDO 的表达和活性。我们认为 RSV 激活 IDO 可能是过敏性疾病发展的潜在机制。
