Gill Navkiran, Deacon Philip M, Lichty Brian, Mossman Karen L, Ashkar Ali A
Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University Health Sciences Centre, Hamilton L8N 3Z5, Ontario, Canada.
J Virol. 2006 Oct;80(20):9943-50. doi: 10.1128/JVI.01036-06.
Toll-like receptors (TLRs) constitute a family of innate receptors that recognize and respond to a wide spectrum of microorganisms, including fungi, bacteria, viruses, and protozoa. Previous studies have demonstrated that ligands for TLR3 and TLR9 induce potent innate antiviral responses against herpes simplex virus type 2 (HSV-2). However, the factor(s) involved in this innate protection is not well-defined. Here we report that production of beta interferon (IFN-beta) but not production of IFN-alpha, IFN-gamma, or tumor necrosis factor alpha (TNF-alpha) strongly correlates with innate protection against HSV-2. Local delivery of poly(I:C) and CpG oligodeoxynucleotides induced significant production of IFN-beta in the genital tract and provided complete protection against intravaginal (IVAG) HSV-2 challenge. There was no detectable IFN-beta in mice treated with ligands for TLR4 or TLR2, and these mice were not protected against subsequent IVAG HSV-2 challenge. There was no correlation between levels of TNF-alpha or IFN-gamma in the genital tract and protection against IVAG HSV-2 challenge following TLR ligand delivery. Both TNF-alpha(-/-) and IFN-gamma(-/-) mice were protected against IVAG HSV-2 challenge following local delivery of poly(I:C). To confirm that type I interferon, particularly IFN-beta, mediates innate protection, mice unresponsive to type I interferons (IFN-alpha/betaR(-/-) mice) and mice lacking IFN regulatory factor-3 (IRF-3(-/-) mice) were treated with poly(I:C) and then challenged with IVAG HSV-2. There was no protection against HSV-2 infection following poly(I:C) treatment of IFN-alpha/betaR(-/-) or IRF-3(-/-) mice. Local delivery of murine recombinant IFN-beta protected C57BL/6 and IRF-3(-/-) mice against IVAG HSV-2 challenge. Results from these in vivo studies clearly suggest a strong correlation between IFN-beta production and innate antiviral immunity against HSV-2.
Toll样受体（TLRs）构成了一类天然受体家族，可识别并响应多种微生物，包括真菌、细菌、病毒和原生动物。先前的研究表明，TLR3和TLR9的配体可诱导针对2型单纯疱疹病毒（HSV-2）的强大天然抗病毒反应。然而，参与这种天然保护的因素尚未明确界定。在此，我们报告β干扰素（IFN-β）的产生与针对HSV-2的天然保护密切相关，而IFN-α、IFN-γ或肿瘤坏死因子α（TNF-α）的产生则不然。聚肌苷酸:聚胞苷酸（poly(I:C)）和CpG寡脱氧核苷酸的局部递送可诱导生殖道中显著的IFN-β产生，并提供针对阴道内（IVAG）HSV-2攻击的完全保护。在用TLR4或TLR2配体处理的小鼠中未检测到IFN-β，并且这些小鼠未受到后续IVAG HSV-2攻击的保护。生殖道中TNF-α或IFN-γ的水平与TLR配体递送后针对IVAG HSV-2攻击的保护之间没有相关性。在局部递送poly(I:C)后，TNF-α基因敲除（-/-）和IFN-γ基因敲除（-/-）小鼠均受到IVAG HSV-2攻击的保护。为了证实I型干扰素，特别是IFN-β介导天然保护，对I型干扰素无反应的小鼠（IFN-α/β受体基因敲除（-/-）小鼠）和缺乏IFN调节因子3（IRF-3基因敲除（-/-）小鼠）用poly(I:C)处理，然后用IVAG HSV-2攻击。在用poly(I:C)处理IFN-α/β受体基因敲除（-/-）或IRF-3基因敲除（-/-）小鼠后，未观察到对HSV-2感染的保护作用。局部递送小鼠重组IFN-β可保护C5 BL/6和IRF-3基因敲除（-/-）小鼠免受IVAG HSV-2攻击这项体内研究的结果清楚地表明，IFN-β产生与针对HSV-2的天然抗病毒免疫之间存在密切相关性。
