Microglia innate immune response contributes to the antiviral defense and blood-CSF barrier function in human choroid plexus organoids during HSV-1 infection.
Microglia innate immune response contributes to the antiviral defense and blood-CSF barrier function in human choroid plexus organoids during HSV-1 infection.
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DOI：
10.1002/jmv.28472
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发表时间：
2023-02
影响因子：
12.7
通讯作者：
Zhao, Zhen
中科院分区：
文献类型：
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作者：
Qiao, Haowen;Chiu, Yuanpu;Liang, Xinyan;Xia, Shangzhou;Ayrapetyan, Mariam;Liu, Siqi;He, Cuiling;Song, Ruocen;Zeng, Jianxiong;Deng, Xiangxue;Yuan, Weiming;Zhao, Zhen
脉络膜丛（ChP）是脑脊液的来源。ChP-CSF系统不仅为大脑提供了必要的缓冲，而且还可以作为废物清除的水槽。在脓毒症期间，病原体和宿主免疫细胞可以削弱ChP屏障并进入大脑，导致脑功能障碍，即脓毒症相关的脑噬症。在这里，我们使用人类ChP类器官（ChPO）来模拟单纯疱疹病毒1型（HSV‐1）感染，发现ChP上皮细胞对HSV‐1高度敏感。由于目前的ChPO模型缺乏功能性先天免疫成分，特别是小胶质细胞，我们下一步开发了一种新的含有小胶质细胞的ChPO模型，发现小胶质细胞可以有效地限制HSV - 1感染并保护ChPO中的上皮屏障。此外，我们发现先天免疫环GMP - AMP合成酶(cGAS) -STING途径及其下游干扰素反应是必不可少的，因为cGAS抑制剂RU.512或STING抑制剂H‐151会破坏小胶质细胞的抗病毒功能，并恶化类器官的ChP屏障。这些结果共同表明，cGAS-STING通路协调ChP的抗病毒反应，并有助于治疗败血症或相关神经系统疾病。
The choroid plexus (ChP) is the source of cerebrospinal fluid (CSF). The ChP–CSF system not only provides the necessary cushion for the brain but also works as a sink for waste clearance. During sepsis, pathogens and host immune cells can weaken the ChP barrier and enter the brain, causing cerebral dysfunctions known as sepsis‐associated encephalophagy. Here, we used human ChP organoid (ChPO) to model herpes simplex virus type 1 (HSV‐1) infection and found ChP epithelial cells were highly susceptible to HSV‐1. Since the current ChPO model lacks a functional innate immune component, particularly microglia, we next developed a new microglia‐containing ChPO model, and found microglia could effectively limit HSV‐1 infection and protect epithelial barrier in ChPOs. Furthermore, we found the innate immune cyclic GMP‐AMP synthase (cGAS)–STING pathway and its downstream interferon response were essential, as cGAS inhibitor RU.512 or STING inhibitor H‐151 abolished microglia antiviral function and worsened ChP barrier in organoids. These results together indicated that cGAS–STING pathway coordinates antiviral response in ChP and contributes to treating sepsis or related neurological conditions.
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DOI：
10.1038/nrn3921
发表时间：
2015-08
期刊：
Nature reviews. Neuroscience
影响因子：
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作者：
Lun MP;Monuki ES;Lehtinen MK
通讯作者：
Lehtinen MK
影响因子：
2.9
作者：
Deffner F;Scharr M;Klingenstein S;Klingenstein M;Milazzo A;Scherer S;Wagner A;Hirt B;Mack AF;Neckel PH
通讯作者：
Neckel PH
影响因子：
23.9
作者：
Bershteyn M;Nowakowski TJ;Pollen AA;Di Lullo E;Nene A;Wynshaw-Boris A;Kriegstein AR
通讯作者：
Kriegstein AR
影响因子：
64.5
作者：
Dani N;Herbst RH;McCabe C;Green GS;Kaiser K;Head JP;Cui J;Shipley FB;Jang A;Dionne D;Nguyen L;Rodman C;Riesenfeld SJ;Prochazka J;Prochazkova M;Sedlacek R;Zhang F;Bryja V;Rozenblatt-Rosen O;Habib N;Regev A;Lehtinen MK
通讯作者：
Lehtinen MK
DOI：
10.1007/s00018-022-04314-1
发表时间：
2022-05-19
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
通讯作者：
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