Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection
Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection
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DOI：
10.1172/jci33940
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发表时间：
2008-05-01
影响因子：
15.9
通讯作者：
Hochrein, Hubertus
中科院分区：
文献类型：
--
作者：
Samuelsson, Christofer;Hausmann, Juergen;Hochrein, Hubertus
痘病毒，如天花的病原体，已经开发出多种策略来抑制免疫反应，包括抑制DC的激活。由于痘病毒是一种大的DNA病毒，我们推测DC对它们的检测可能涉及内体DNA识别受体TLR9。事实上，我们在这里已经证明，鼠痘的病原体--蜕皮病病毒(ECTV)的DC识别完全取决于TLR9。缺乏TLR9的小鼠对ECTV感染的易感性显著增加，这一事实突显了TLR9的重要性。相反，我们发现强减毒痘病毒修饰的痘苗病毒安卡拉(MVA)通过TLR9依赖和非依赖途径激活DC。因此，我们测试了是否可以利用MVA更广泛的诱导免疫反应来保护小鼠免受ECTV的致命感染。事实上，在注射致死剂量ECTV的同时给予MVA可以保护小鼠免于死亡。重要的是，MVA还拯救了TLR9缺陷小鼠，如果在感染ECTV后整整两天给予MVA。因此，这些数据表明TLR9在防御痘病毒方面发挥了重要作用。此外，暴露后应用MVA可预防致死性痘病毒感染。
Poxviruses such as the causative agent of smallpox have developed multiple strategies to suppress immune responses, including the suppression of DC activation. Since poxviruses are large DNA viruses, we hypothesized that their detection by DCs may involve the endosomal DNA recognition receptor TLR9. Indeed, we have shown here that DC recognition of ectromelia virus (ECTV), the causative agent of mousepox, completely depended on TLR9. The importance of TLR9 was highlighted by the fact that mice lacking TLR9 showed drastically increased susceptibility to infection with ECTV. In contrast, we found that the strongly attenuated poxvirus modified vaccinia virus Ankara (MVA) activated DCs by both TLR9-dependent and -independent pathways. We therefore tested whether we could use the broader induction of immune responses by MVA to protect mice from a lethal infection with ECTV. Indeed, MVA given at the same time as a lethal dose of ECTV protected mice from death. Importantly, MVA also rescued TLR9-deficient mice if administered 2 full days after an otherwise lethal infection with ECTV. Therefore, these data suggest an essential role for TLR9 in the defense against poxviruses. In addition, postexposure application of MVA may protect against lethal poxvirus infection.