Gill Navkiran, Rosenthal Kenneth L, Ashkar Ali A
Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada.
J Virol. 2005 Apr;79(7):4470-8. doi: 10.1128/JVI.79.7.4470-4478.2005.
Interleukin-15 (IL-15) is essential for the development, maturation, and function of NK and NKT cells, which are critical components of the innate immune defense against viral infections. We recently showed that mice lacking IL-15 and/or NK/NKT cells are significantly more susceptible to intravaginal (IVAG) herpes simplex virus type 2 (HSV-2) infection than control mice. For this study, we examined whether IL-15 has any direct antiviral activity, independent of NK/NKT cells, in innate protection against HSV-2 infection. A sensitive enzyme-linked immunosorbent assay for murine IL-15 was developed and used to show that IVAG HSV-2 infection induces IL-15 in vaginal washes. Using immunohistochemistry, we detected IL-15-positive cells in the submucosa and vaginal epithelium following IVAG HSV-2 infection. Local, but not systemic, delivery of murine recombinant IL-15 (mrIL-15) to the genital mucosae of IL-15(-/-) and RAG-2(-/-) gamma(c)(-/-) mice, which both lack NK and NKT cells, resulted in significant reductions in HSV-2 titers in genital washes and 60% survival following IVAG HSV-2 challenge. Furthermore, we showed that IL-15 is important for CpG oligodeoxynucleotide (ODN)-induced innate protection against genital HSV-2 infection. While 100% of CpG ODN-treated RAG2(-/-) gamma(c)(-/-) mice, which are capable of producing IL-15 but lack NK/NKT cells, survived an IVAG HSV-2 challenge, only 60% of CpG ODN-treated IL-15(-/-) mice survived, and all of these mice had similar vaginal viral titers to those in control mice by day 3 postchallenge. Lastly, a treatment of RAW264.7 cells with mrIL-15 induced the production of tumor necrosis factor alpha and beta interferon (IFN-beta), but not IFN-alpha, and significantly protected them against HSV-2 infection in vitro. The results of these studies indicate that IL-15 can act independently of NK/NKT cells in mediating the innate defense against viral infection.
白细胞介素-15（IL-15）对于自然杀伤细胞（NK细胞）和自然杀伤T细胞（NKT细胞）的发育、成熟及功能至关重要，而NK细胞和NKT细胞是针对病毒感染的固有免疫防御的关键组成部分。我们最近发现，缺乏IL-15和/或NK/NKT细胞的小鼠比对照小鼠更易受到阴道内（IVAG）单纯疱疹病毒2型（HSV-2）感染。在本研究中，我们检测了IL-15在针对HSV-2感染的固有保护中是否具有任何独立于NK/NKT细胞的直接抗病毒活性。我们开发了一种针对小鼠IL-15的灵敏酶联免疫吸附测定法，并用于显示IVAG HSV-2感染可诱导阴道冲洗液中产生IL-15。通过免疫组织化学方法，我们在IVAG HSV-2感染后的黏膜下层和阴道上皮中检测到了IL-15阳性细胞。将小鼠重组IL-15（mrIL-15）局部而非全身递送至缺乏NK细胞和NKT细胞的IL-15基因敲除（IL-15(-/-)）小鼠及重组激活基因2缺陷（RAG-2(-/-)）γ链缺陷（gamma(c)(-/-)）小鼠的生殖黏膜，可使生殖器冲洗液中的HSV-2滴度显著降低，并使IVAG HSV-2攻击后的存活率达到60%。此外，我们还表明IL-15对于CpG寡脱氧核苷酸（ODN）诱导的针对生殖器HSV-2感染的固有保护很重要。虽然100%经CpG ODN处理的能够产生IL-15但缺乏NK/NKT细胞的RAG2(-/-) gamma(c)(-/-)小鼠在IVAG HSV-2攻击后存活下来，但经CpG ODN处理的IL-15(-/-)小鼠只有60%存活，并且在攻击后第3天，所有这些小鼠的阴道病毒滴度与对照小鼠相似。最后，用mrIL-15处理RAW264.7细胞可诱导肿瘤坏死因子α和β干扰素（IFN-β）的产生，但不诱导IFN-α的产生，并在体外显著保护它们免受HSV-2感染。这些研究结果表明，IL-15在介导针对病毒感染的固有防御中可独立于NK/NKT细胞发挥作用。
