Local Delivery of CpG Oligodeoxynucleotides Induces Rapid Changes in the Genital Mucosa and Inhibits Replication, but Not Entry, of Herpes Simplex Virus Type 2

Abstract

Mucosal surfaces are the entry sites for the vast majority of infectious pathogens and provide the first line of defense against infection. In addition to the epithelial barrier, the innate immune system plays a key role in recognizing and rapidly responding to invading pathogens via innate receptors, such as Toll-like receptors (TLR). Bacterial CpG DNA, a potent activator of innate immunity, is recognized by TLR9. Here, we confirm that local mucosal, but not systemic, delivery of CpG oligodeoxynucleotides (ODN) to the genital tract protects mice from a subsequent lethal vaginal herpes simplex virus type 2 (HSV-2) challenge. Since these effects were so local in action, we examined the genital mucosa. Local delivery of CpG ODN induced rapid proliferation and thickening of the genital epithelium and caused significant recruitment of inflammatory cells to the submucosa. Local CpG ODN treatment also resulted in inhibition of HSV-2 replication but had no effect on HSV-2 entry into the genital mucosa. CpG ODN-induced protection against HSV-2 was not associated with early increases in gamma interferon (IFN-␥) secretion in the genital tract, and CpG ODN-treated IFN-␥ ؊/؊ mice were protected from subsequent challenge with a lethal dose of HSV-2. Treatment of human HEK-293 cells transfected with murine TLR9 showed that the antiviral activity of CpG ODN was mediated through TLR9. These studies suggest that local induction of mucosal innate immunity can provide protection against sexually transmitted infections, such as HSV-2 or possibly human immunodeficiency virus, at the mucosal surfaces.

Mucosal Administration of CpG Oligodeoxynucleotide Elicits Strong CC and CXC Chemokine Responses in the Vagina and Serves as a Potent Th1-Tilting Adjuvant for Recombinant gD2 Protein Vaccination against Genital Herpes

“…Further, a single vaginal dose of CpG ODN confers potent innate immune protection against genital herpes (1,6). We show in the present study that the local mucosal administration of CpG ODN is associated with a rapid and strong increase in the CC chemokines MIP-1␣, MIP-1␤, and RANTES and the CXC chemokines IP-10 and MIP-2 in both the vagina and the draining lymph nodes.…”

“…Interestingly, some of these immune components were demonstrated to play a significant role in innate immune protection against genital herpes (9,20). We and others have shown that pretreatment of mice with a single vaginal dose of CpG ODN, without any exogenous viral antigen codelivery, affords significant innate immune protection against primary genital herpes infection and disease (1,6,21). The observed protection was found to induce the development of an HSV-2-specific memory response affording sterilizing immunity against reinfection (6).…”

TLR2 and TLR9 Synergistically Control Herpes Simplex Virus Infection in the Brain

“…Additionally, the TLR2 Ϫ/Ϫ mice responded to the infection with an impaired inflammatory response (17,21,23). TLR9 has been examined in the vaginal infection model, with several studies showing a protective effect of locally administered TLR9 ligand CpG before HSV infection (33,(43)(44)(45)(46)(47). For TLR9 Ϫ/Ϫ mice one study found these mice to be more susceptible to HSV-2 (27), yet another found no differences (22).…”

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

“…First, CpG ODN induces active proliferation of the genital epithelium (5). Second, a variety of inflammatory cells have been shown to accumulate in vaginal mucosa, including NK cells, CD11b + F4/80 + myeloid cells, and CD11b + CD11c + DCs (5,8).…”