Novel strategies for targeting innate immune responses to influenza.
Novel strategies for targeting innate immune responses to influenza.
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我们先前报道了TLR 4-/-小鼠对小鼠适应的A/PR/8/34（PR 8）流感诱导的致死性是难治的，并且当在感染后2天开始给予时，治疗性给予TLR 4拮抗剂Acetoran阻断PR 8诱导的致死性和急性肺损伤（ALI）。在此，我们扩展了这些发现：抗TLR 4或TLR 2特异性IgG疗法也赋予野生型（WT）小鼠免受致死性PR 8感染的显著保护。如果在PR 8感染前3小时开始治疗，并每天持续4天，则阿托莫兰不能保护WT和TLR 4-/-小鼠，这意味着阿托莫兰必须阻断病毒诱导的非TLR 4信号，这是保护所需的。从机制上讲，我们确定了（i）阿托莫兰在体外阻断HMGB 1介导的TLR 4依赖性信号传导，在体内阻断循环HMGB 1，HMGB 1抑制剂可预防PR 8;（ii）阿托莫兰抑制与ALI相关的肺水肿;（iii）IL-1β显著促进PR 8诱导的致死性，如IL-1受体拮抗剂（IL-1 Ra）治疗的部分保护作用所证明。当在感染后4天开始施用阿托莫兰和抗病毒药物奥司他韦时，实现了针对PR 8诱导的致死性的协同保护。Escherichoran治疗不能阻止对随后的PR 8攻击的适应性免疫应答的发展。总的来说，我们的数据支持针对流感感染的宿主靶向治疗方法的潜力。
We previously reported that TLR4-/- mice are refractory to mouse-adapted A/PR/8/34 (PR8) influenza-induced lethality and that therapeutic administration of the TLR4 antagonist, Eritoran, blocked PR8-induced lethality and acute lung injury (ALI) when given starting 2 days post-infection. Herein, we extend these findings: anti-TLR4- or TLR2-specific IgG therapy also conferred significant protection of wild-type (WT) mice from lethal PR8 infection. If treatment is initiated 3 h prior to PR8 infection and continued daily for 4 days, Eritoran failed to protect WT and TLR4-/- mice, implying that Eritoran must block a virus-induced, non-TLR4 signal that is required for protection. Mechanistically, we determined that (i) Eritoran blocks HMGB1-mediated, TLR4-dependent signaling in vitro and circulating HMGB1 in vivo, and an HMGB1 inhibitor protects against PR8; (ii) Eritoran inhibits pulmonary lung edema associated with ALI, (iii) IL-1β contributes significantly to PR8-induced lethality, as evidenced by partial protection by IL-1 receptor antagonist (IL-1Ra) therapy. Synergistic protection against PR8-induced lethality was achieved when Eritoran and the anti-viral drug, oseltamivir, were administered starting 4 days post-infection. Eritoran treatment does not prevent development of an adaptive immune response to subsequent PR8 challenge. Overall, our data support the potential of a host-targeted therapeutic approach to influenza infection.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
DOI：
10.1038/nri3665
发表时间：
2014-05
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.1019378108
发表时间：
2011-03-29
影响因子：
11.1
作者：
Ichinohe, Takeshi;Pang, Iris K.;Iwasaki, Akiko
通讯作者：
Iwasaki, Akiko
影响因子：
3.8
作者：
Leung, Y. H. Connie;Nicholls, John M.;Peiris, J. S. Malik
通讯作者：
Peiris, J. S. Malik
影响因子：
7.4
作者：
Kadl A;Sharma PR;Chen W;Agrawal R;Meher AK;Rudraiah S;Grubbs N;Sharma R;Leitinger N
通讯作者：
Leitinger N