Molecular and cellular dissection of the pathogenesis of herpes simplex encephalitis with iPSC-derived CNS and PNS cells

用 iPSC 衍生的 CNS 和 PNS 细胞对单纯疱疹脑炎发病机制进行分子和细胞解剖

基本信息

  • 批准号:
    10596586
  • 负责人:
  • 金额:
    $ 62.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-09-20 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Forebrain HSE (which develops via olfactory neurons) in otherwise healthy children can result from inborn errors of the TLR3 pathway (mutations in TLR3, UNC93B1, TRIF, TRAF3, TBK1, and IRF3), whereas brainstem HSE (via trigeminal (TG) neurons) can result from inborn errors of RNA lariat metabolism (DBR1). Children with a broader defect of impaired production of (NEMO) or response to all IFNs (STAT1) are prone to HSE and other infections. We analyzed the cellular basis of HSE by deriving peripheral and central nervous system (PNS and CNS) cells from induced pluripotent stem cells (iPSC) (NIH R01NS072381). TLR3-deficient forebrain cortical neurons and oligodendrocyte precursors have impaired anti-HSV-1 cell-intrinsic immunity, unlike astrocytes and neural stem cells; microglial cells were not tested. Moreover, iPSC-derived TG neurons do not rely on TLR3 to control HSV-1; olfactory neurons were not tested. Finally, TLR3 controls both basal IFN levels and early steps of anti-HSV-1 immunity in cortical neurons. Childhood HSE results thus from inborn errors of non-hematopoietic, CNS-specific, cell-intrinsic immunity, affecting cortical neurons and oligodendrocytes in particular. We have since identified new forebrain HSE-causing genes that are connected to the TLR3-IFN circuit (MEX3B, IFNAR1), the TLR3-necroptosis pathway (RIPK3), and of unknown function (SNORA31, TMEFF1). In this renewal application, we hypothesize that genetic etiologies of forebrain HSE impair intrinsic immunity in cortical but not olfactory neurons, and in oligodendrocytes and probably microglial cells, and DBR1 deficiency impairs intrinsic immunity in brainstem and/or TG neurons and probably microglial cells. First, we will assess the responses of iPSC-derived olfactory and cortical neurons, and other CNS cells, from controls and patients mutated in new forebrain HSE-causing genes, to TLR3, IFN-α/β or IFN-λ, and HSV-1 stimulation. Second, we will study RNA lariat accumulation, immunity to HSV-1 infection, and responses to IFN-α/β or IFN- λ, in control and DBR1-deficient iPSC-differentiated TG and brainstem neurons. Third, the role of microglial cells in forebrain vs brainstem HSE will be assessed by studying the responses to TLR3 agonists, IFN-α/β, IFN-λ and HSV-1, in isolation and in neuronal co-culture. Patient and isogenic iPSC lines in which the mutation is corrected or introduced by gene editing will be used. Cell-intrinsic immunity to HSV-1 and its molecular basis will be analyzed. Exciting preliminary data have been obtained, including (1) novel genetic etiologies of HSE, (2) novel mechanisms by which TLR3 controls HSV-1 in cortical neurons, and (3) novel protocols to differentiate brainstem neurons and microglial cells. The expand of this human iPSC-based study of HSE will enable us to dissect in greater breadth and depth its molecular and cellular basis in children with inborn errors of CNS-intrinsic immunity to HSV-1.
项目摘要 单纯疱疹病毒1型(HSV-1)脑炎(HSE)是西方国家最常见的散发性病毒性脑炎。健康儿童的前脑HSE(通过嗅觉神经元发育)可能是由TLR 3通路(TLR 3,UNC 93 B1,TRIF,TRAF 3,TBK 1和IRF 3突变)的先天性错误引起的,而脑干HSE(通过三叉神经(TG)神经元)可能是由RNA代谢(DBR 1)的先天性错误引起的。具有NEMO产生受损或对所有IFN(STAT 1)反应受损的更广泛缺陷的儿童容易发生HSE和其他感染。我们通过从诱导多能干细胞(iPSC)(NIH R 01 NS 072381)衍生外周和中枢神经系统(PNS和CNS)细胞来分析HSE的细胞基础。与星形胶质细胞和神经干细胞不同,TLR 3缺陷的前脑皮质神经元和少突胶质细胞前体具有受损的抗HSV-1细胞内在免疫力;未测试小胶质细胞。此外,iPSC衍生的TG神经元不依赖于TLR 3来控制HSV-1;嗅觉神经元未被测试。最后,TLR 3控制皮质神经元中的基础IFN水平和抗HSV-1免疫的早期步骤。因此,儿童HSE是由非造血、CNS特异性、细胞内在免疫的先天性缺陷引起的,特别是影响皮质神经元和少突胶质细胞。此后,我们发现了与TLR 3-IFN回路(MEX 3B,IFNAR 1),TLR 3-坏死性凋亡通路(RIPK 3)和未知功能(SNORA 31,TMEFF 1)相关的新的前脑HSE引起基因。在此更新申请中,我们假设前脑HSE的遗传病因损害皮质但不是嗅觉神经元,以及少突胶质细胞和可能的小胶质细胞中的固有免疫,并且DBR 1缺乏损害脑干和/或TG神经元和可能的小胶质细胞中的固有免疫。首先,我们将评估iPSC衍生的嗅觉和皮质神经元以及其他CNS细胞对TLR 3、IFN-α/β或IFN-λ和HSV-1刺激的反应,这些细胞来自对照组和在新的前脑HSE引起基因中突变的患者。其次,我们将研究对照和DBR 1缺陷iPSC分化的TG和脑干神经元中的RNA脂质体积累、对HSV-1感染的免疫力以及对IFN-α/β或IFN- λ的应答。第三,将通过研究在分离和神经元共培养中对TLR 3激动剂、IFN-α/β、IFN-λ和HSV-1的应答来评估小胶质细胞在前脑相对于脑干HSE中的作用。将使用通过基因编辑校正或引入突变的患者和同基因iPSC系。将分析细胞对HSV-1的内在免疫及其分子基础。已经获得了令人兴奋的初步数据,包括(1)HSE的新遗传病因,(2)TLR 3控制皮质神经元中HSV-1的新机制,以及(3)分化脑干神经元和小胶质细胞的新方案。这项基于人类iPSC的HSE研究的扩展将使我们能够更广泛和深入地剖析其在患有CNS先天性缺陷的儿童中的分子和细胞基础-对HSV-1的内在免疫。

项目成果

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Jean-Laurent Casanova其他文献

Jean-Laurent Casanova的其他文献

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{{ truncateString('Jean-Laurent Casanova', 18)}}的其他基金

Human Genetics of Tuberculosis
结核病的人类遗传学
  • 批准号:
    10430226
  • 财政年份:
    2021
  • 资助金额:
    $ 62.45万
  • 项目类别:
Human Genetics of Tuberculosis
结核病的人类遗传学
  • 批准号:
    10268806
  • 财政年份:
    2021
  • 资助金额:
    $ 62.45万
  • 项目类别:
Inborn errors of immunity in patients with life-threatening COVID-19
危及生命的 COVID-19 患者先天性免疫缺陷
  • 批准号:
    10655372
  • 财政年份:
    2021
  • 资助金额:
    $ 62.45万
  • 项目类别:
Inborn errors of immunity in patients with life-threatening COVID-19
危及生命的 COVID-19 患者先天性免疫缺陷
  • 批准号:
    10278180
  • 财政年份:
    2021
  • 资助金额:
    $ 62.45万
  • 项目类别:
Inborn errors of immunity in patients with life-threatening COVID-19
危及生命的 COVID-19 患者先天性免疫缺陷
  • 批准号:
    10449276
  • 财政年份:
    2021
  • 资助金额:
    $ 62.45万
  • 项目类别:
Human Genetics of Tuberculosis
结核病的人类遗传学
  • 批准号:
    10621305
  • 财政年份:
    2021
  • 资助金额:
    $ 62.45万
  • 项目类别:
Molecular and cellular basis of epidermodysplasia verruciformis
疣状表皮发育不良的分子和细胞基础
  • 批准号:
    10561607
  • 财政年份:
    2020
  • 资助金额:
    $ 62.45万
  • 项目类别:
Monogenic basis of resistance to SARS-CoV2 and predisposition to severe COVID-19
抗 SARS-CoV2 的单基因基础和严重 COVID-19 的易感性
  • 批准号:
    10159675
  • 财政年份:
    2020
  • 资助金额:
    $ 62.45万
  • 项目类别:
Molecular and cellular basis of epidermodysplasia verruciformis
疣状表皮发育不良的分子和细胞基础
  • 批准号:
    10352425
  • 财政年份:
    2020
  • 资助金额:
    $ 62.45万
  • 项目类别:
Molecular and cellular basis of epidermodysplasia verruciformis
疣状表皮发育不良的分子和细胞基础
  • 批准号:
    9887337
  • 财政年份:
    2020
  • 资助金额:
    $ 62.45万
  • 项目类别:

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