Local delivery of CpG oligodeoxynucleotides induces rapid changes in the genital mucosa and inhibits replication, but not entry, of herpes simplex virus type 2
Local delivery of CpG oligodeoxynucleotides induces rapid changes in the genital mucosa and inhibits replication, but not entry, of herpes simplex virus type 2
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DOI：
10.1128/jvi.77.16.8948-8956.2003
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发表时间：
2003-08-01
影响因子：
5.4
通讯作者：
Rosenthal, KL
中科院分区：
文献类型：
--
作者：
Ashkar, AA;Bauer, S;Rosenthal, KL
粘液表面是绝大多数感染性病原体的进入部位，并提供了抵抗感染的第一道防线。除了上皮屏障之外，先天免疫系统在通过先天受体（例如Toll样受体（TLR））识别和快速响应入侵病原体中起关键作用。细菌CpG DNA是先天免疫的有效激活剂，被TLR 9识别。在这里，我们证实，局部粘膜，但不是全身性的，交付的CpG寡脱氧核苷酸（ODN）的生殖道保护小鼠从随后的致命阴道单纯疱疹病毒2型（HSV-2）的挑战。由于这些作用是局部的，我们检查了生殖器粘膜。CpG ODN的局部递送诱导生殖器上皮的快速增殖和增厚，并引起炎性细胞向粘膜下层的显著募集。局部CpG ODN治疗也导致HSV-2复制的抑制，但对HSV-2进入生殖器粘膜没有影响。CpG ODN诱导的抗HSV-2的保护作用与生殖道中γ干扰素（IFN-γ）分泌的早期增加无关，CpG ODN处理的IFN-γ（-/-）小鼠受到保护，免于随后用致死剂量的HSV-2攻击。转染小鼠TLR 9的人HEK-293细胞的处理表明，CpG ODN的抗病毒活性是通过TLR 9介导的。这些研究表明，粘膜先天免疫的局部诱导可以在粘膜表面提供针对性传播感染（例如HSV-2或可能的人类免疫缺陷病毒）的保护。
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 inierferon (IFN-gamma) secretion in the genital tract, and CpG ODN-treated IFN-gamma(-/-) 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.