RIPK3 and caspase 8 collaborate to limit herpes simplex encephalitis.
RIPK3 and caspase 8 collaborate to limit herpes simplex encephalitis.
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DOI：
10.1371/journal.ppat.1010857
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发表时间：
2022-09
期刊：
影响因子：
6.7
通讯作者：
Dix, Richard D.
中科院分区：
文献类型：
--
作者：
Guo, Hongyan;Koehler, Heather S.;Mocarski, Edward S.;Dix, Richard D.
单纯疱疹病毒1型(HSV1)对大脑的侵袭可导致单纯疱疹病毒性脑炎(HSE)的发展，无论采取何种治疗措施，HSE通常都会导致严重的发病率和死亡率。病毒和宿主免疫因素共同决定了HSE的发生和发展。由于包括坏死下垂在内的程序性细胞死亡通路在HSV1相关外周疾病中是重要的抗病毒防御机制，它们在HSV1神经发病机制中也可能发挥关键作用。HSV1编码的ICP6可在感染人类细胞时阻止受体相互作用蛋白激酶3(RIPK3)介导的坏死性下垂，但它也可作为小鼠细胞坏死性下垂的物种依赖诱导物，从而限制病毒复制。因此，我们使用已建立的HSE小鼠模型来研究RIPK3介导的坏死性下垂对HSV1神经发病机制的影响。在接种角膜HSV1后，RIPK3基因敲除小鼠与野生型小鼠相比，对HSE的易感性增加，这表明RIPK3有助于限制HSE的进展。RIPK3介导的对HSE的防御被发现不依赖于驱动坏死性下垂所必需的激酶结构域，这意味着RIPK3的死亡无关功能对HSE具有保护作用。相反，促坏死酶功能RIPK3有助于限制角膜组织中的病毒复制，这意味着RIPK3在限制HSV1方面具有组织特异性功能。对限制HSE的激酶非依赖性机制的进一步评估表明，RIPK3信号伙伴caspase 8有助于限制HSE的神经发病。Caspase8和RIPK3缺失导致的HSE易感性增加与趋化因子、细胞因子和抗病毒淋巴细胞向脑内募集的水平降低有关。我们得出结论，RIPK3以组织特异性的方式促进宿主对HSV1复制的控制。虽然RIPK3介导的坏死性下垂限制了病毒在角膜内的复制，但在HSE神经发病过程中，RIPK3与caspase 8协同诱导的非激酶诱导炎症限制了病毒在脑内的复制。坏死性下垂是一种程序性细胞死亡途径，其功能是限制病毒在组织内的复制，从而预防或减少临床疾病。RIPK3是一种对坏死性下垂的激活至关重要的激酶，但可能通过其他不依赖于激酶的方式来限制病毒复制。因此，我们进行了研究，以探讨RIPK3可能参与由单纯疱疹病毒1型(HSV1)引起的一种称为单纯疱疹病毒性脑炎(HSE)的致命性脑炎的神经发病机制。使用HSE的小鼠模型，其中HSV1感染是通过角膜接种随后传播到大脑的神经病毒来完成的，我们证明了RIPK3以组织特异性的方式通过角膜和脑内不同的机制限制病毒复制。HSV1复制在角膜组织内受RIPK3激酶介导的坏死性上睑下垂的限制，而HSV1复制在脑组织内受RIPK3激酶非依赖性活性的限制，这需要与caspase 8协作。这种协作刺激脑内抗病毒免疫反应的招募，从而导致坏死性下垂非依赖性炎症，提供对HSV1诱导的HSE的保护。我们的发现扩大了RIPK3在HSV1神经发病机制中的作用，并可能为HSE的治疗开辟新的途径。
Invasion of the brain by herpes simplex virus 1 (HSV1) can lead to the development of herpes simplex encephalitis (HSE) that is often associated with significant morbidity and mortality regardless of therapeutic intervention. Both virus and host immune factors dictate HSE onset and progression. Because programmed cell death pathways including necroptosis are important antiviral defense mechanisms in HSV1-associated peripheral diseases, they might also play critical roles in HSV1 neuropathogenesis. HSV1-encoded ICP6 prevents receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis during infection of human cells, but it also acts as a species-dependent inducer of necroptosis in murine cells and thereby restricts virus replication. We therefore used an established mouse model of HSE to investigate RIPK3-mediated necroptosis impact on HSV1 neuropathogenesis. Following corneal HSV1 inoculation, RIPK3 knockout mice showed increased susceptibility to HSE when compared with wildtype mice indicating RIPK3 helps to limit HSE progression. RIPK3-mediated defense against HSE was found to be independent of the kinase domain necessary to drive necroptosis implicating that a death independent function of RIPK3 protects against HSE. Conversely the pro-necroptotic kinase function RIPK3 served to limit viral replication in corneal tissue implicating a tissue-specific RIPK3 function in limiting HSV1. Further evaluation of the kinase-independent mechanism to restrict HSE revealed that the RIPK3 signaling partner, caspase 8, contributes to limiting HSE neuropathogenesis. Increased HSE susceptibility from loss of caspase 8 and RIPK3 correlated with decreased levels of chemokines, cytokines, and antiviral lymphocytes recruitment to the brain. We conclude that RIPK3 contributes toward host control of HSV1 replication in a tissue-specific fashion. Whereas RIPK3-mediated necroptosis restricts virus replication within the cornea, kinase-independent induction of inflammation by RIPK3 in collaboration with caspase 8 restricts virus replication within the brain during HSE neuropathogenesis. Necroptosis is a programmed cell death pathway whose function is to restrict virus replication within tissue and thereby prevent or minimize clinical disease. RIPK3 is a kinase critical to the activation of necroptosis, but may contribute to the restriction of virus replication in other kinase-independent ways. We therefore performed studies to investigate possible mechanisms whereby RIPK3 might contribute to the neuropathogenesis of a fatal inflammation of the brain called herpes simplex encephalitis (HSE) caused by herpes simplex virus 1 (HSV1). Using a mouse model of HSE in which HSV1 infection is done by cornea inoculation with subsequent neural virus spread to the brain, we showed that RIPK3 restricts virus replication by different mechanisms within cornea and brain in a tissue-specific fashion. Whereas HSV1 replication is restricted within corneal tissue by RIPK3 kinase-mediated necroptosis, HSV1 replication is restricted within brain tissue by RIPK3 kinase-independent activity that requires collaboration with caspase 8. This collaboration stimulates the recruitment of antiviral immune responses within the brain that leads to necroptosis-independent inflammation which provides protection against HSV1-induced HSE. Our findings extend the role of RIPK3 during HSV1 neuropathogenesis and may open up new avenues for the treatment of HSE.
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影响因子：
5.4
作者：
Hayes, Cooper K.;Giraldo, Daniel;Longnecker, Richard
通讯作者：
Longnecker, Richard
DOI：
10.4049/jimmunol.181.9.6427
发表时间：
2008-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
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通讯作者：
Mocarski ES
影响因子：
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作者：
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通讯作者：
Chan FK
影响因子：
5.4
作者：
Guo H;Kaiser WJ;Mocarski ES
通讯作者：
Mocarski ES
影响因子：
11.4
作者：
Chattopadhyay, Saurabh;Marques, Joao T.;Sen, Ganes C.
通讯作者：
Sen, Ganes C.