TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16
TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16
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DOI：
10.4049/jimmunol.178.5.3186
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Tommasino, Massimo
中科院分区：
文献类型：
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作者：
Hasan, Uzma A.;Bates, Elizabeth;Tommasino, Massimo
宫颈癌的发展与高危粘膜人乳头瘤病毒 (HPV) 类型的持续感染有关。这种 dsDNA 病毒的 E6 和 E7 主要癌蛋白在细胞周期失调、细胞凋亡和适应性免疫监视中发挥着关键作用。在这项研究中，我们首次表明，高危亚群中致癌性最强的 HPV 16 型（HPV16）通过影响 TLR 的表达来干扰先天免疫。用 HPV16 E6 和 E7 重组逆转录病毒感染人原代角质形成细胞会抑制 TLR9 转录，从而导致 TLR9 调节途径的功能丧失。在 HPV16 阳性癌症衍生细胞系和原发性宫颈癌中也取得了类似的发现，表明该事件也发生在体内环境中。有趣的是，来自低风险 HPV 6 型的 E6 和 E7 无法下调 TLR9 启动子。此外，来自高危 HPV 18 型的 E6 和 E7 已知在宿主体内的持久性不如 HPV16，与 HPV16 相比，其抑制 TLR9 转录的效率也较低。此外，源自 HPV16 E6 DNA 序列的 CpG 基序激活了 TLR9，表明该病毒能够通过随后下调的受体启动先天反应。这项研究揭示了 HPV16 通过放松 TLR9 转录本来抑制宿主免疫反应的新机制，提供了证据表明消除先天反应可能是 HPV 介导的致癌事件的关键步骤。
Cervical cancer development is linked to the persistent infection by high-risk mucosal human papillomaviruses (HPVs) types. The E6 and E7 major oncoproteins from this dsDNA virus play a key role in the deregulation of the cell cycle, apoptosis, and adaptive immune surveillance. In this study, we show for the first time that HPV type 16 (HPV16), the most carcinogenic type among the high-risk subgroup, interferes with innate immunity by affecting the expression of TLRs. Infection of human primary keratinocytes with HPV16 E6 and E7 recombinant retroviruses inhibits TLR9 transcription and hence functional loss of TLR9-regulated pathways. Similar findings were achieved in HPV16-positive cancer-derived cell lines and primary cervical cancers, demonstrating that this event occurs also in an in vivo context. Interestingly, E6 and E7 from the low-risk HPV type 6 are unable to down-regulate the TLR9 promoter. In addition, E6 and E7 from the high-risk HPV type 18, which are known to persist less competently in the host than HPV16, have reduced efficiency compared with HPV16 in inhibiting TLR9 transcription. Furthermore, a CpG motif derived from the HPV16 E6 DNA sequence activated TLR9, indicating this virus is able to initiate innate responses via the receptor it later down-regulates. This study reveals a novel mechanism used by HPV16 to suppress the host immune response by deregulating the TLR9 transcript, providing evidence that abolishing innate responses may be a crucial step involved in the carcinogenic events mediated by HPVs.