NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection.
NK/ILC1 cells mediate neuroinflammation and brain pathology following congenital CMV infection.
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DOI：
10.1084/jem.20201503
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发表时间：
2021-05-03
期刊：
影响因子：
--
通讯作者：
Jonjić S
中科院分区：
文献类型：
--
作者：
Kveštak D;Juranić Lisnić V;Lisnić B;Tomac J;Golemac M;Brizić I;Indenbirken D;Cokarić Brdovčak M;Bernardini G;Krstanović F;Rožmanić C;Grundhoff A;Krmpotić A;Britt WJ;Jonjić S
利用先天性巨细胞病毒感染的小鼠模型，证据提供了NK和ILC1细胞在大脑中的致病作用。虽然脑浸润性先天免疫细胞不能控制感染，但它们协调病理性炎症反应，导致小脑发育改变。先天性人类巨细胞病毒（cHCMV）感染大脑与广泛的神经认知后遗症有关。我们利用新生小鼠巨细胞病毒（MCMV）感染作为一个可靠的模型，概括了cHCMV感染的许多方面，包括弥播性感染、中枢神经系统感染、神经发育改变和感音神经性听力丧失。我们之前已经表明，炎症的缓解可以阻止小脑发育的改变，这表明宿主炎症因子是神经发育缺陷的关键驱动因素。在这里，我们发现MCMV感染导致小胶质细胞来源的趋化因子CXCL9/CXCL10的表达急剧增加，CXCL9/CXCL10以依赖cxcr3的方式招募NK和ILC1细胞进入大脑。令人惊讶的是，浸润大脑的先天免疫细胞不仅不能控制大脑中的病毒感染，而且还能协调病理性炎症反应，从而导致小脑形态发生的延迟。我们的研究结果表明NK和ILC1细胞是发育中的中枢神经系统对病毒感染的免疫病理反应的主要介质，这可以通过抗ifn -γ抗体来预防。
Using a mouse model of congenital cytomegalovirus infection, evidence is provided for a pathogenic role of NK and ILC1 cells in the brain. Although brain-infiltrating innate immune cells fail to control infection, they orchestrate pathological inflammatory responses that lead to altered cerebellar development. Congenital human cytomegalovirus (cHCMV) infection of the brain is associated with a wide range of neurocognitive sequelae. Using infection of newborn mice with mouse cytomegalovirus (MCMV) as a reliable model that recapitulates many aspects of cHCMV infection, including disseminated infection, CNS infection, altered neurodevelopment, and sensorineural hearing loss, we have previously shown that mitigation of inflammation prevented alterations in cerebellar development, suggesting that host inflammatory factors are key drivers of neurodevelopmental defects. Here, we show that MCMV infection causes a dramatic increase in the expression of the microglia-derived chemokines CXCL9/CXCL10, which recruit NK and ILC1 cells into the brain in a CXCR3-dependent manner. Surprisingly, brain-infiltrating innate immune cells not only were unable to control virus infection in the brain but also orchestrated pathological inflammatory responses, which lead to delays in cerebellar morphogenesis. Our results identify NK and ILC1 cells as the major mediators of immunopathology in response to virus infection in the developing CNS, which can be prevented by anti–IFN-γ antibodies.
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影响因子：
30.5
作者：
Goldmann T;Wieghofer P;Jordão MJ;Prutek F;Hagemeyer N;Frenzel K;Amann L;Staszewski O;Kierdorf K;Krueger M;Locatelli G;Hochgerner H;Zeiser R;Epelman S;Geissmann F;Priller J;Rossi FM;Bechmann I;Kerschensteiner M;Linnarsson S;Jung S;Prinz M
通讯作者：
Prinz M
影响因子：
14.9
作者：
Grigoriev IV;Nikitin R;Haridas S;Kuo A;Ohm R;Otillar R;Riley R;Salamov A;Zhao X;Korzeniewski F;Smirnova T;Nordberg H;Dubchak I;Shabalov I
通讯作者：
Shabalov I
DOI：
10.1007/978-1-4939-3572-7_13
发表时间：
2016-01-01
期刊：
DATA MINING TECHNIQUES FOR THE LIFE SCIENCES
影响因子：
--
作者：
Dobin, Alexander;Gingeras, Thomas R.
通讯作者：
Gingeras, Thomas R.
DOI：
10.4049/jimmunol.181.3.2111
发表时间：
2008-08-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bantug GR;Cekinovic D;Bradford R;Koontz T;Jonjic S;Britt WJ
通讯作者：
Britt WJ
影响因子：
15.3
作者：
Dorfman, JR;Raulet, DH
通讯作者：
Raulet, DH