A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN-based vaginal microbicide

Abstract

Topical microbicides represent a promising new approach to preventing HIV and other sexually transmitted infections. TLR agonists are ideal candidates for microbicides, as they trigger a multitude of antiviral genes effective against a broad range of viruses. Although vaginal application of CpG oligodeoxynucleotides (ODNs) and poly I:C has been shown to protect mice from genital herpes infection, the mechanism by which these agents provide protection remains unclear. Here, we show that plasmacytoid DCs (pDCs) are required for CpG ODNmediated protection against lethal vaginal challenge with herpes simplex virus type 2 (HSV-2). Moreover, we demonstrate that cells of both the hematopoietic and stromal compartments must respond to CpG ODN via TLR9 and to type I IFNs through IFN-αβ receptor (IFN-αβR) for protection. Thus, crosstalk between pDCs and vaginal stromal cells provides for optimal microbicide efficacy. Our results imply that temporally and spatially controlled targeting of CpG ODN to pDCs and epithelial cells can potentially maximize their effectiveness as microbicides while minimizing the associated inflammatory responses.

An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

“…Moreover, depletion of pDCs did not affect the antiviral activity of IFN-in vivo. This in contrast to the mechanism through which type I IFN mediates antiviral protection in the same model, where responsiveness to IFN-␣␤ is required in both hemopoietic and nonhemopoietic cells for complete antiviral protection following CpG ODN treatment (41). When we examined the ability of IFN-to induce an antiviral state in vaginal cells we found that treatment of cells with this cytokine strongly inhibited replication of HSV-2.…”

“…2). It has been shown that HSV-2 replication occurs exclusively in epithelial cells during vaginal infection in mice (44), and that pDCs are essential for triggering antiviral activity by CpG in this model (41). Therefore, we wanted to examine whether expression of IL-28R␣ on cells from the hemopoietic vs the nonhemopoietic compartment contributed to antiviral defense.…”

Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue

“…Vaginal fluids were collected between days 0 and 7 of HSV-2 infection using calcium alginate swabs and PBS. Viral titers were obtained by titration of vaginal wash samples on Vero cell monolayer as described previously (39,40). IFN-γ levels were detected from vaginal fluids (19) or tissue (41) as previously described.…”

Interferons as Biomarkers and Effectors: Lessons Learned from Animal Models

“…pDCs are rapidly recruited to the vagina within 24 h of HSV-2 infection, where they produce high levels of IFN−α in response to TLR9 recognition of CpG, which is found abundantly in HSV-2 genomes [72]. pDCs deficient in TLR9 are unable to produce IFN−α upon HSV-2 stimulation [72,73] and, in vivo, TLR9-/-mice infected with HSV-2 have no detectable circulating IFN−α resulting in the rapid pathology and reduced survival of these mice [74,75]. Consistent with the importance of type I IFNs in the anti-HSV response, IFNAR1-/-mice have increased susceptibility to HSV-2 infection, with elevated viral replication [76].…”