Tenland Erik, Håkansson Gisela, Alaridah Nader, Lutay Nataliya, Rönnholm Anna, Hallgren Oskar, Westergren-Thorsson Gunilla, Godaly Gabriela
Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University, Lund, Sweden.
Department of Translational Medicine, Division of Clinical Microbiology, Lund University, Lund, Sweden.
PLoS One. 2016 Oct 10;11(10):e0164431. doi: 10.1371/journal.pone.0164431. eCollection 2016.
Mycobacterium bovis bacilli Calmette-Guerin (BCG) is used as a benchmark to compare the immunogenicity of new vaccines against tuberculosis. This live vaccine is administered intradermal, but several new studies show that changing the route to mucosal immunisation represents an improved strategy. We analysed the immunomodulatory functions of BCG on human neutrophils and primary airway epithelial cells (AECs), as the early events of mucosal immune activation are unclear. Neutrophils and the primary epithelial cells were found to express the IL-17A receptor subunit IL-17RA, while the expression of IL-17RE was only observed on epithelial cells. BCG stimulation specifically reduced neutrophil IL-17RA and epithelial IL-17RE expression. BCG induced neutrophil extracellular traps (NETs), but did not have an effect on apoptosis as measured by transcription factor forkhead box O3 (FOXO3). BCG stimulation of AECs induced CXCL8 secretion and neutrophil endothelial passage towards infected epithelia. Infected epithelial cells and neutrophils were not found to be a source of IL-17 cytokines or the interstitial collagenase MMP-1. However, the addition of IFNγ or IL-17A to BCG stimulated primary epithelial cells increased epithelial IL-6 secretion, while the presence of IFNγ reduced neutrophil recruitment. Using our model of mucosal infection we revealed that BCG induces selective mucosal innate immune responses that could lead to induction of vaccine-mediated protection of the lung.
牛分枝杆菌卡介苗（BCG）被用作比较新型结核病疫苗免疫原性的基准。这种活疫苗通过皮内注射给药，但几项新研究表明，将给药途径改为黏膜免疫是一种更好的策略。由于黏膜免疫激活的早期事件尚不清楚，我们分析了BCG对人中性粒细胞和原代气道上皮细胞（AECs）的免疫调节功能。发现中性粒细胞和原代上皮细胞表达白细胞介素17A受体亚基IL-17RA，而IL-17RE仅在上皮细胞上表达。BCG刺激特异性降低中性粒细胞IL-17RA和上皮细胞IL-17RE的表达。BCG诱导中性粒细胞胞外陷阱（NETs）形成，但通过转录因子叉头框O3（FOXO3）检测，对细胞凋亡没有影响。BCG刺激AECs诱导CXCL8分泌，并促使中性粒细胞穿过内皮细胞向受感染的上皮细胞移动。未发现受感染的上皮细胞和中性粒细胞是白细胞介素17细胞因子或间质胶原酶MMP-1的来源。然而，在BCG刺激的原代上皮细胞中添加干扰素γ（IFNγ）或白细胞介素17A可增加上皮细胞白细胞介素6的分泌，而IFNγ的存在会减少中性粒细胞的募集。利用我们的黏膜感染模型，我们发现BCG可诱导选择性黏膜固有免疫反应，这可能导致诱导疫苗介导的肺部保护。
