Tumor necrosis factor (TNF) protects resistant C57BL/6 mice against herpes simplex virus-induced encephalitis independently of signaling via TNF receptor 1 or 2
Tumor necrosis factor (TNF) protects resistant C57BL/6 mice against herpes simplex virus-induced encephalitis independently of signaling via TNF receptor 1 or 2
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DOI：
10.1128/jvi.02243-06
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发表时间：
2007-02-01
影响因子：
5.4
通讯作者：
Cantin, Edouard
中科院分区：
文献类型：
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作者：
Lundberg, Patric;Welander, Paula V.;Cantin, Edouard
肿瘤坏死因子（TNF）是一种多功能细胞因子，在诱导和调节宿主先天性和适应性免疫反应中发挥作用。不同病毒，特别是疱疹病毒家族成员，采用不同的策略来阻断 TNF 反应，这反映了 TNF 抗病毒机制的重要性。 TNF 通过两种受体结合并发出信号：Tnfrsf1a（TNF 受体 1 [TNFR1] 或 p55）和 Tnfrsf1b（TNFR2 或 p75）。我们在此报告，具有耐药性 C57BL/6 遗传背景的 TNF-/- 小鼠感染单纯疱疹病毒 1 (HSV-1) 会导致对致命性 HSV 脑炎 (HSE) 的易感性显着增加（P < 0.0001，对数秩检验），并且神经组织中病毒水平升高的持续时间较长。相比之下，尽管p55(-/-)N13小鼠神经组织中的病毒滴度升高至与TNF-/-小鼠相当的水平，但p55(-/-)N13小鼠与对照C57BL/6小鼠一样具有抵抗力(P > 0.05)。在 C57BL/6 小鼠中，使用可溶性 TNFR1 (sTNFR1) 体内中和 TNF 或消耗巨噬细胞，致死性 HSE 的发生率显着增加（分别为 P = 0.0038 和 P = 0.0071）。引人注目的是，通过使用三种独立的方法（用可溶性 p55 受体、抗 TNF 单克隆抗体或体内针对 TNF 的小干扰 RNA 治疗）体内中和 HSV-1 感染的 p55(-/-) p75(-/-) 小鼠中的 TNF，导致死亡率显着增加 (P = 0.005)，其程度与用 sTNFR1 治疗的 C57BL/6 小鼠的死亡率相当。 0.0018）。总体而言，这些结果表明，虽然 TNF 是抵抗致命 HSE 所必需的，但 p55 和 p75 受体都是可有可无的。 TNF 究竟如何介导 p55(-/-) p75(-/-) 小鼠 HSV-1 死亡的保护作用仍有待确定。
Tumor necrosis factor (TNF) is a multifunctional cytokine that has a role in induction and regulation of host innate and adaptive immune responses. The importance of TNF antiviral mechanisms is reflected by the diverse strategies adopted by different viruses, particularly members of the herpesvirus family, to block TNF responses. TNF binds and signals through two receptors, Tnfrsf1a (TNF receptor 1 [TNFR1], or p55) and Tnfrsf1b (TNFR2, or p75). We report here that herpes simplex virus 1 (HSV-1) infection of TNF-/- mice on the resistant C57BL/6 genetic background results in significantly increased susceptibility (P < 0.0001, log rank test) to fatal HSV encephalitis (HSE) and prolonged persistence of elevated levels of virus in neural tissues. In contrast, although virus titers in neural tissues of p55(-/-)N13 mice were elevated to levels comparable to what was found for the TNF-/- mice, the p55(-/-)N13 mice were as resistant as control C57BL/6 mice (P > 0.05). The incidence of fatal HSE was significantly increased by in vivo neutralization of TNF using soluble TNFR1 (sTNFR1) or depletion of macrophages in C57BL/6 mice (P = 0.0038 and P = 0.0071, respectively). Strikingly, in vivo neutralization of TNF in HSV-1-infected p55(-/-) p75(-/-) mice by use of three independent approaches (treatment with soluble p55 receptor, anti-TNF monoclonal antibody, or in vivo small interfering RNA against TNF) resulted in significantly increased mortality rates (P = 0.005), comparable in magnitude to those for C57BL/6 mice treated with sTNFR1 (P = 0.0018). Overall, these results indicate that while TNF is required for resistance to fatal HSE, both p55 and p75 receptors are dispensable. Precisely how TNF mediates protection against HSV-1 mortality in p55(-/-) p75(-/-) mice remains to be determined.