Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
Department of Medical Microbiology and Immunology, University of California, Davis, California, USA.
J Virol. 2018 Nov 12;92(23). doi: 10.1128/JVI.01219-18. Print 2018 Dec 1.
Plasmacytoid dendritic cells (pDCs) are innate immune cells with high antiviral activity triggered by Toll-like receptor 7 (TLR-7) and TLR-9 stimulation. Moreover, they are important mediators between innate and adaptive immunity. Although nowadays there is available an effective therapeutic arsenal against hepatitis C virus (HCV), a protective vaccine is not available. We have analyzed the pDCs' response to HCV infection in a hepatitis C virus (HCV)-Huh7.5 virus-cell system, which allows completion of the virus infectious cycle. pDCs were cocultured following human immunodeficiency virus (HIV) aldrithiol-2 (AT-2 [TLR-7 agonist]) inactivation and CpG (TLR-9 agonist) stimulation. We employed three virus derivatives-wild-type Jc1, interferon (IFN)-resistant virus IR, and high-replicative-fitness virus P100-in order to explore additional IFN-α-related virus inhibition mechanisms. pDCs inhibited HCV infectivity and replication and produced IFN-α. After TLR-7 and TLR-9 stimulation, inhibition of infectivity and IFN-α production by pDCs were enhanced. TLR-7 stimulation drove higher TNF-related apoptosis-inducing ligand (TRAIL) expression in pDCs. Additionally, TLR-7- and TLR-9-stimulated pDCs exhibited a mature phenotype, improving the antigen presentation and lymph node homing-related markers. In conclusion, pDCs could serve as a drug target against HCV in order to improve antiviral activity and as an enhancer of viral immunization. We implemented a coculture system of pDCs with HCV-infected hepatoma cell line, Huh7.5. We used three HCV derivatives in order to gain insight into pDCs' behavior against HCV and associated antiviral mechanisms. The results with this cell coculture system support the capacity of pDCs to inhibit HCV replication and infectivity mainly via IFN-α, but also through additional mechanisms associated with pDC maturation. We provided evidence that TLR agonists can enhance antiviral pDCs' function and can induce phenotypic changes that may facilitate the interplay with other immune cells. These findings suggest the possibility of including TLR agonists in the strategies of HCV vaccine development.
浆细胞样树突状细胞 (pDCs) 是具有高抗病毒活性的先天免疫细胞，可被 Toll 样受体 7 (TLR-7) 和 TLR-9 刺激触发。此外，它们是先天免疫和适应性免疫之间的重要介质。尽管目前有针对丙型肝炎病毒 (HCV) 的有效治疗武器，但尚无保护性疫苗。我们在丙型肝炎病毒 (HCV)-Huh7.5 病毒-细胞系统中分析了 pDCs 对 HCV 感染的反应，该系统允许完成病毒感染周期。pDCs 在人类免疫缺陷病毒 (HIV) aldritiol-2 (TLR-7 激动剂) 失活和 CpG (TLR-9 激动剂) 刺激后进行共培养。我们采用了三种病毒衍生物-野生型 Jc1、干扰素 (IFN) 抗性病毒 IR 和高复制适应性病毒 P100-以探索额外的 IFN-α 相关病毒抑制机制。pDCs 抑制 HCV 感染性和复制并产生 IFN-α。在 TLR-7 和 TLR-9 刺激后，pDCs 抑制感染性和 IFN-α 产生的能力增强。TLR-7 刺激导致 pDCs 中 TNF 相关凋亡诱导配体 (TRAIL) 的表达增加。此外，TLR-7 和 TLR-9 刺激的 pDCs 表现出成熟的表型，改善了抗原呈递和淋巴结归巢相关标志物。总之，pDCs 可作为 HCV 的药物靶点，以提高抗病毒活性并作为病毒免疫增强剂。我们实施了 pDCs 与 HCV 感染的肝癌细胞系 Huh7.5 的共培养系统。我们使用了三种 HCV 衍生物，以深入了解 pDCs 对 HCV 的行为和相关抗病毒机制。该细胞共培养系统的结果支持 pDCs 主要通过 IFN-α 抑制 HCV 复制和感染性的能力，但也通过与 pDC 成熟相关的其他机制。我们提供的证据表明，TLR 激动剂可以增强抗病毒 pDCs 的功能，并诱导可能促进与其他免疫细胞相互作用的表型变化。这些发现表明在 HCV 疫苗开发策略中加入 TLR 激动剂的可能性。
