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.