The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS route for SARS-CoV-2

被引：162

作者：

Krasemann, Susanne ^{[1
,2
]}

Haferkamp, Undine ^{[3
,19
]}

Pfefferle, Susanne ^{[4
,5
,6
]}

Woo, Marcel S. ^{[7
]}

Heinrich, Fabian ^{[8
]}

Schweizer, Michaela ^{[9
]}

Appelt-Menzel, Antje ^{[10
,11
]}

Cubukova, Alevtina ^{[11
]}

Barenberg, Janica ^{[3
,19
]}

Leu, Jennifer ^{[3
,19
]}

Hartmann, Kristin ^{[1
,2
]}

Thies, Edda ^{[1
]}

Littau, Jessica Lisa ^{[1
]}

Sepulveda-Falla, Diego ^{[1
]}

Zhang, Liang ^{[12
]}

Ton, Kathy ^{[12
]}

Liang, Yan ^{[12
]}

Matschke, Jakob ^{[1
]}

Ricklefs, Franz ^{[13
]}

Sauvigny, Thomas ^{[13
]}

Sperhake, Jan ^{[8
]}

Fitzek, Antonia ^{[8
]}

Gerhartl, Anna ^{[14
]}

Brachner, Andreas ^{[14
]}

Geiger, Nina ^{[20
]}

Koenig, Eva-Maria ^{[20
]}

Bodem, Jochen ^{[20
]}

Franzenburg, Soren ^{[15
]}

Franke, Andre ^{[15
]}

Moese, Stefan ^{[16
]}

Mueller, Franz-Josef ^{[17
]}

Geisslinger, Gerd ^{[18
,19
]}

Claussen, Carsten ^{[3
,19
]}

Kannt, Aimo ^{[18
,19
]}

Zaliani, Andrea ^{[3
,19
]}

Gribbon, Philip ^{[3
,19
]}

Ondruschka, Benjamin ^{[8
]}

Neuhaus, Winfried ^{[14
]}

Friese, Manuel A. ^{[7
]}

Glatzel, Markus ^{[1
]}

Pless, Ole ^{[3
,19
]}

机构：

[1] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, D-20246 Hamburg, Germany

[2] Univ Med Ctr Hamburg Eppendorf, Expt Pathol Core Facil, D-20246 Hamburg, Germany

[3] Fraunhofer Inst Translat Med & Pharmacol ITMP, Discovery Res ScreeningPort, D-22525 Hamburg, Germany

[4] Univ Med Ctr Hamburg Eppendorf, Inst Med Microbiol Virol & Hyg, D-20246 Hamburg, Germany

[5] Leibniz Inst Trop Med, Bernhard Nocht Inst, D-20359 Hamburg, Germany

[6] German Ctr Infect Res, Partner Site Hamburg Borstel Lubeck Riems, D-20359 Hamburg, Germany

[7] Univ Med Ctr Hamburg Eppendorf, Inst Neuroimmunol & Multiple Sclerosis, D-20251 Hamburg, Germany

[8] Univ Med Ctr Hamburg Eppendorf, Inst Legal Med, D-20246 Hamburg, Germany

[9] Univ Med Ctr Hamburg Eppendorf, Ctr Mol Neurobiol ZMNH, Morphol & Electron Microscopy Core Facil, D-20251 Hamburg, Germany

[10] Univ Hosp Wuzburg, Chair Tissue Engn & Regenerat Med TERM, D-97070 Wurzburg, Germany

[11] Fraunhofer Inst Silicate Res ISC, Translat Ctr Regenerat Therapies TLC RT, D-97070 Wurzburg, Germany

[12] Nanostring Technol, Seattle, WA 98109 USA

[13] Univ Med Ctr Hamburg Eppendorf, Dept Neurosurg, D-20246 Hamburg, Germany

[14] AIT Austrian Inst Technol GmbH, A-1210 Vienna, Austria

[15] Univ Klinikum Schleswig Holstein, Inst Clin Mol Biol, D-24105 Kiel, Germany

[16] Neurimmune AG, CH-8952 Schlieren, Switzerland

[17] Zentrum Integrat Psychiat ZIP GmbH, Univ Klinikum Schleswig Holstein, D-24105 Kiel, Germany

[18] Fraunhofer Inst Translat Med & Pharmacol ITMP, D-60596 Frankfurt, Germany

[19] Fraunhofer Cluster Excellence Immune Mediated Dis, D-60596 Frankfurt, Germany

[20] Univ Wurzburg, Inst Virol & Immunobiol, D-97078 Wurzburg, Germany

来源：

STEM CELL REPORTS | 2022年 / 17卷 / 02期

关键词：

ENDOTHELIAL-CELLS; PACKAGE; UNIT; RNA;

D O I：

10.1016/j.stemcr.2021.12.011

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected in patients' brain tissues, its entry routes and resulting consequences are not well understood. Here, we show a pronounced upregulation of interferon signaling pathways of the neurovascular unit in fatal COVID-19. By investigating the susceptibility of human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) to SARS-CoV-2 infection, we found that BCECs were infected and recapitulated transcriptional changes detected in vivo. While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active replication and transcellular transport of virus across the blood-brain barrier (BBB) in vitro. Moreover, entry of SARS-CoV-2 into BCECs could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for SARS-CoV-2 brain entry across the BBB resulting in increased interferon signaling.

引用

页码：307 / 320

页数：14

共 58 条

[1] Zika virus crosses an in vitro human blood brain barrier model [J].

Alimonti, Judie B. ;

Ribecco-Lutkiewicz, Maria ;

Sodja, Caroline ;

Jezierski, Anna ;

Stanimirovic, Danica B. ;

Liu, Qing ;

Haqqani, Arsalan S. ;

Conlan, Wayne ;

Bani-Yaghoub, Mahmud .

FLUIDS AND BARRIERS OF THE CNS, 2018, 15

[2] Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells [J].

Appelt-Menzel, Antje ;

Cubukova, Alevtina ;

Guenther, Katharina ;

Edenhofer, Frank ;

Piontek, Joerg ;

Krause, Gerd ;

Stueber, Tanja ;

Walles, Heike ;

Neuhaus, Winfried ;

Metzger, Marco .

STEM CELL REPORTS, 2017, 8 (04) :894-906

[3] The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice [J].

Bao, Linlin ;

Deng, Wei ;

Huang, Baoying ;

Gao, Hong ;

Liu, Jiangning ;

Ren, Lili ;

Wei, Qiang ;

Yu, Pin ;

Xu, Yanfeng ;

Qi, Feifei ;

Qu, Yajin ;

Li, Fengdi ;

Lv, Qi ;

Wang, Wenling ;

Xue, Jing ;

Gong, Shuran ;

Liu, Mingya ;

Wang, Guanpeng ;

Wang, Shunyi ;

Song, Zhiqi ;

Zhao, Linna ;

Liu, Peipei ;

Zhao, Li ;

Ye, Fei ;

Wang, Huijuan ;

Zhou, Weimin ;

Zhu, Na ;

Zhen, Wei ;

Yu, Haisheng ;

Zhang, Xiaojuan ;

Guo, Li ;

Chen, Lan ;

Wang, Conghui ;

Wang, Ying ;

Wang, Xinming ;

Xiao, Yan ;

Sun, Qiangming ;

Liu, Hongqi ;

Zhu, Fanli ;

Ma, Chunxia ;

Yan, Lingmei ;

Yang, Mengli ;

Han, Jun ;

Xu, Wenbo ;

Tan, Wenjie ;

Peng, Xiaozhong ;

Jin, Qi ;

Wu, Guizhen ;

Qin, Chuan .

NATURE, 2020, 583 (7818) :830-+

[4] The olfactory nerve is not a likely route to brain infection in COVID-19: a critical review of data from humans and animal models [J].

Butowt, Rafal ;

Meunier, Nicolas ;

Bryche, Bertrand ;

von Bartheld, Christopher S. .

ACTA NEUROPATHOLOGICA, 2021, 141 (06) :809-822

[5]

Buzhdygan TP, 2020, NEUROBIOL DIS, V146, DOI [10.1016/j.nbd.2020.105131, 10.1101/2020.06.15.150912]

[6] Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity [J].

Cantuti-Castelvetri, Ludovico ;

Ojha, Ravi ;

Pedro, Liliana D. ;

Djannatian, Minou ;

Franz, Jonas ;

Kuivanen, Suvi ;

van der Meer, Franziska ;

Kallio, Katri ;

Kaya, Tugberk ;

Anastasina, Maria ;

Smura, Teemu ;

Levanov, Lev ;

Szirovicza, Leonora ;

Tobi, Allan ;

Kallio-Kokko, Hannimari ;

Osterlund, Pamela ;

Joensuu, Merja ;

Meunier, Frederic A. ;

Butcher, Sarah J. ;

Winkler, Martin Sebastian ;

Mollenhauer, Brit ;

Helenius, Ari ;

Gokce, Ozgun ;

Teesalu, Tambet ;

Hepojoki, Jussi ;

Vapalahti, Olli ;

Stadelmann, Christine ;

Balistreri, Giuseppe ;

Simons, Mikael .

SCIENCE, 2020, 370 (6518) :856-+

[7] Elevated ACE-2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication [J].

Chen, Mengfei ;

Shen, Wenjuan ;

Rowan, Nicholas R. ;

Kulaga, Heather ;

Hillel, Alexander ;

Ramanathan, Murugappan ;

Lane, Andrew P. .

EUROPEAN RESPIRATORY JOURNAL, 2020, 56 (03)

[8] Neuropilin-1 is a host factor for SARS-CoV-2 infection [J].

Daly, James L. ;

Simonetti, Boris ;

Klein, Katja ;

Chen, Kai-En ;

Williamson, Maia Kavanagh ;

Anton-Plagaro, Carlos ;

Shoemark, Deborah K. ;

Simon-Gracia, Lorena ;

Bauer, Michael ;

Hollandi, Reka ;

Greber, Urs F. ;

Horvath, Peter ;

Sessions, Richard B. ;

Helenius, Ari ;

Hiscox, Julian A. ;

Teesalu, Tambet ;

Matthews, David A. ;

Davidson, Andrew D. ;

Collins, Brett M. ;

Cullen, Peter J. ;

Yamauchi, Yohei .

SCIENCE, 2020, 370 (6518) :861-+

[9] COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters [J].

de Melo, Guilherme Dias ;

Lazarini, Francoise ;

Levallois, Sylvain ;

Hautefort, Charlotte ;

Michel, Vincent ;

Larrous, Florence ;

Verillaud, Benjamin ;

Aparicio, Caroline ;

Wagner, Sebastien ;

Gheusi, Gilles ;

Kergoat, Lauriane ;

Kornobis, Etienne ;

Donati, Flora ;

Cokelaer, Thomas ;

Hervochon, Remi ;

Madec, Yoann ;

Roze, Emmanuel ;

Salmon, Dominique ;

Bourhy, Herve ;

Lecuit, Marc ;

Lledo, Pierre-Marie .

SCIENCE TRANSLATIONAL MEDICINE, 2021, 13 (596)

[10] Barrier Properties and Transcriptome Expression in Human iPSC-Derived Models of the Blood-Brain Barrier [J].

Delsing, Louise ;

Donnes, Pierre ;

Sanchez, Jost ;

Clausen, Maryam ;

Voulgaris, Dimitrios ;

Falk, Anna ;

Herland, Anna ;

Brolen, Gabriella ;

Zetterberg, Henrik ;

Hicks, Ryan ;

Synnergren, Jane .

STEM CELLS, 2018, 36 (12) :1816-1827

← 1 2 3 4 5 6 →