RIPK3 interacts with MAVS to regulate type I IFN-mediated immunity to Influenza A virus infection.
RIPK3 interacts with MAVS to regulate type I IFN-mediated immunity to Influenza A virus infection.
复制标题
DOI：
10.1371/journal.ppat.1006326
复制
发表时间：
2017-04
期刊：
影响因子：
6.7
通讯作者：
Divangahi M
中科院分区：
文献类型：
--
作者：
Downey J;Pernet E;Coulombe F;Allard B;Meunier I;Jaworska J;Qureshi S;Vinh DC;Martin JG;Joubert P;Divangahi M
I型干扰素途径在宿主防御和对病毒感染的耐受中起关键作用，因此需要精细的调节机制。RIPK 3介导的坏死性凋亡已显示参与抗病毒免疫。然而，RIPK 3在对甲型流感病毒（IAV）的免疫中的确切作用知之甚少。与其他人一样，我们在此表明Ripk 3-/-小鼠对IAV感染高度易感，表现出肺病毒载量升高以及发病率和死亡率升高。出乎意料的是，这种易感性与RIKP 3缺陷型巨噬细胞（Mφ）无法在感染小鼠的肺中产生I型IFN有关。在体外感染IAV的Mφ中，我们发现RIPK 3通过与MAVS相互作用并限制RIPK 1与MAVS的相互作用在转录上调节I型IFN，并且通过激活蛋白激酶R（PKR）在转录后调节I型IFN-β mRNA稳定性。总的来说，我们的研究结果表明RIPK 3在调节Mφ介导的I型IFN抗病毒免疫中的新作用，独立于其在坏死性凋亡中的传统作用。甲型流感病毒（IAV）是一种肺部病原体，通过季节性流行和偶尔的高致命性大流行对人类健康构成重大威胁。I型IFN是流感病毒感染的抗病毒免疫的重要组成部分，肺巨噬细胞是I型IFN的主要来源。最近，我们已经表明，程序性巨噬细胞死亡（凋亡）在流感感染的免疫中起着关键作用。有趣的是，另一种细胞死亡程序，称为坏死性凋亡，也涉及通过受体相互作用丝氨酸/苏氨酸蛋白激酶3（RIPK 3）控制病毒感染。在本研究中，我们定义了一个新的作用RIPK 3在调节I型IFN途径，以防止致命的IAV感染，这是独立的坏死性凋亡。RIPK 3在转录和转录后水平调节I型IFN信号传导以隔离病毒复制并保护宿主免受流感感染。因此，操纵RIPK 3途径为开发抗IAV治疗提供了新的途径。
The type I interferon pathway plays a critical role in both host defense and tolerance against viral infection and thus requires refined regulatory mechanisms. RIPK3-mediated necroptosis has been shown to be involved in anti-viral immunity. However, the exact role of RIPK3 in immunity to Influenza A Virus (IAV) is poorly understood. In line with others, we, herein, show that Ripk3-/- mice are highly susceptible to IAV infection, exhibiting elevated pulmonary viral load and heightened morbidity and mortality. Unexpectedly, this susceptibility was linked to an inability of RIKP3-deficient macrophages (Mφ) to produce type I IFN in the lungs of infected mice. In Mφ infected with IAV in vitro, we found that RIPK3 regulates type I IFN both transcriptionally, by interacting with MAVS and limiting RIPK1 interaction with MAVS, and post-transcriptionally, by activating protein kinase R (PKR)—a critical regulator of IFN-β mRNA stability. Collectively, our findings indicate a novel role for RIPK3 in regulating Mφ-mediated type I IFN anti-viral immunity, independent of its conventional role in necroptosis. Influenza A virus (IAV) is a pulmonary pathogen that presents a significant threat to human health through seasonal epidemics and occasional, highly lethal pandemics. Type I IFN is an essential component of anti-viral immunity to influenza infection and pulmonary macrophages are the major source of type I IFN. Recently, we have shown that programmed macrophage cell death (apoptosis) plays a key role in immunity to influenza infection. Interestingly, another cell death program, termed necroptosis, has been also implicated in control of viral infection via receptor-interacting serine/threonine protein kinase 3 (RIPK3). In the present study, we define a novel role of RIPK3 in regulating the type I IFN pathway to protect against lethal IAV infection, which is independent of necroptosis. RIPK3 regulates type I IFN signaling at both the transcriptional and post-transcriptional levels to sequester viral replication and protect the host against influenza infection. Thus, manipulation of the RIPK3 pathways poses a novel avenue in the development of anti-IAV treatments.