Influenza A virus infection induces indoleamine 2,3-dioxygenase (IDO) expression and modulates subsequent inflammatory mediators in nasal epithelial cells

Abstract

Background: Nasal epithelial cells are the first site of encounter of the influenza virus, and their innate immune response might define subsequent inflammatory direction.

Aims/objectives: We used metabolomics analysis to identify metabolic changes and the regulation of inflammatory cytokines in nasal epithelial cells upon influenza virus infection.

Material and methods: We cultured nasal epithelial cells using air-liquid interface (ALI) model. Influenza virus (PR8) infection followed by metabolomic analysis was performed. Furthermore, cytokine expression was analyzed by cytokine array and RT-qPCR.

Results: Metabolomic analysis revealed depletion of the tryptophan and accumulation of its metabolite, kynurenine, within 48 h. The major enzyme involved in the tryptophan metabolic pathway, indoleamine 2,3-dioxygenase (IDO), was overexpressed after infection. Cytokine expression array after infection showed increased levels of IL-1α, CCL2, IL-6, CXCL10, CCL5, and CXCL11, and after using 1-methyltryptophan (1-MT) as inhibitor, the expression levels of IL-6 and G-CSF were reduced.

Conclusions and significance: Viral infection results in depletion of tryptophan and accumulation of kynurenine via increased cellular IDO activity. Inhibition of IDO activity or replenishment of tryptophan by local application may be a good therapeutic strategy for limiting the initial damage caused by influenza virus in nasal epithelial cells.

Chinese abstract

背景：鼻上皮细胞是流感病毒的第一个接触部位, 其固有的免疫反应可能决定了随后的炎症方向。

目的：应用代谢组学分析研究流感病毒感染后鼻上皮细胞的代谢变化及炎性细胞因子的调节。

材料与方法：采用气液界面（ALI）模型培养鼻上皮细胞。流感病毒（PR8）感染后进行代谢组学分析。用细胞因子阵列和RT-qPCR分析细胞因子的表达。

结果：代谢组学分析显示48小时内色氨酸的消耗和代谢物kynurenine的积累。色氨酸代谢途径中的主要酶吲哚胺2,3-双加氧酶（IDO）在感染后高表达。感染后细胞因子表达谱显示IL-1α、CCL2、IL-6、CXCL10、CCL5和CXCL11的水平升高, 而且使用1-甲基色氨酸（1-MT）作为抑制剂后, IL-6和G-CSF表达水平降低。

结论与意义：病毒感染通过增加细胞IDO活性而导致色氨酸的消耗和酪氨酸的积累。局部应用抑制IDO活性或补充色氨酸可能是限制流感病毒对鼻上皮细胞最初损伤的一种较好的治疗策略。

Keywords:

• Nasal epithelial cells
• innate immunity
• influenza virus
• tryptophan
• kynurenine
• IDO

Acknowledgements

The authors thank the staff of the RCF7 Lab, Department of Medical Research, National Taiwan University Hospital for technical support during the study.

Author contributions

Lin YT and Yeh TH designed the study, collected the data and drafted the manuscript. Yeh TH designed the study, analyzed the data and critically revised the manuscript. Lin CF coordinated the study and participated in data analysis, drafted the manuscript and critically revised the manuscript. All authors read and approved the final manuscript.

Disclosure statement

The authors have no conflict of interests to disclose.

Additional information

Funding

This study was financially supported by the Ministry of Science and Technology (MOST 106-2314-B-002-119).