Department of Pathology & Molecular Medicine, McMaster Immunology Research Centre, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
PLoS One. 2012;7(4):e35866. doi: 10.1371/journal.pone.0035866. Epub 2012 Apr 24.
Upon viral recognition, innate and adaptive antiviral immune responses are initiated by genital epithelial cells (ECs) to eradicate or contain viral infection. Such responses, however, are often accompanied by inflammation that contributes to acquisition and progression of sexually transmitted infections (STIs). Hence, interventions/factors enhancing antiviral protection while reducing inflammation may prove beneficial in controlling the spread of STIs. Serine antiprotease trappin-2 (Tr) and its cleaved form, elafin (E), are alarm antimicrobials secreted by multiple cells, including genital epithelia.
We investigated whether and how each Tr and E (Tr/E) contribute to antiviral defenses against a synthetic mimic of viral dsRNA, polyinosine-polycytidylic acid (polyI:C) and vesicular stomatitis virus. We show that delivery of a replication-deficient adenovector expressing Tr gene (Ad/Tr) to human endometrial epithelial cells, HEC-1A, resulted in secretion of functional Tr, whereas both Tr/E were detected in response to polyI:C. Moreover, Tr/E were found to significantly reduce viral replication by either acting directly on virus or through enhancing polyI:C-driven antiviral protection. The latter was associated with reduced levels of pro-inflammatory factors IL-8, IL-6, TNFα, lowered expression of RIG-I, MDA5 and attenuated NF-κB activation. Interestingly, enhanced polyI:C-driven antiviral protection of HEC-Ad/Tr cells was partially mediated through IRF3 activation, but not associated with higher induction of IFNβ, suggesting multiple antiviral mechanisms of Tr/E and the involvement of alternative factors or pathways.
This is the first evidence of both Tr/E altering viral binding/entry, innate recognition and mounting of antiviral and inflammatory responses in genital ECs that could have significant implications for homeostasis of the female genital tract.
病毒识别后，生殖道上皮细胞（EC）会启动固有和适应性抗病毒免疫反应，以消除或抑制病毒感染。然而，这些反应通常伴随着炎症，从而促进性传播感染（STI）的获得和进展。因此，增强抗病毒保护同时减少炎症的干预/因素可能有助于控制 STI 的传播。丝氨酸蛋白酶抑制剂trappin-2（Tr）及其裂解形式，Elafin（E），是多种细胞（包括生殖道上皮细胞）分泌的警报抗菌肽。
我们研究了 Tr 和 E（Tr/E）是否以及如何有助于针对病毒双链 RNA 模拟物聚肌胞苷酸（polyI:C）和水疱性口炎病毒的抗病毒防御。我们发现，表达 Tr 基因的复制缺陷型腺病毒载体（Ad/Tr）转染人子宫内膜上皮细胞（HEC-1A）后，可分泌功能性 Tr，而 polyI:C 可诱导 Tr/E 的产生。此外，Tr/E 可直接作用于病毒或通过增强 polyI:C 驱动的抗病毒保护来显著抑制病毒复制。后者与促炎因子 IL-8、IL-6、TNFα 水平降低、RIG-I、MDA5 表达下调和 NF-κB 激活减弱有关。有趣的是，HEC-Ad/Tr 细胞中增强的 polyI:C 驱动的抗病毒保护作用部分通过 IRF3 激活介导，但与 IFNβ 的诱导增加无关，这表明 Tr/E 具有多种抗病毒机制，并涉及替代因素或途径。
这是生殖道 EC 中 Tr/E 改变病毒结合/进入、固有识别以及启动抗病毒和炎症反应的首个证据，这可能对女性生殖道的内稳态具有重要意义。
