Neuroinvasion of SARS-CoV-2 in human and mouse brain

被引：679

作者：

Song, Eric ^{[1
]}

Zhang, Ce ^{[2
,3
]}

Israelow, Benjamin ^{[1
,4
]}

Lu-Culligan, Alice ^{[1
]}

Prado, Alba Vieites ^{[5
]}

Skriabine, Sophie ^{[5
]}

Lu, Peiwen ^{[1
]}

Orr-El Weizman ^{[1
]}

Liu, Feimei ^{[1
,6
]}

Dai, Yile ^{[1
]}

Szigeti-Buck, Klara ^{[7
]}

Yasumoto, Yuki ^{[7
]}

Wang, Guilin ^{[8
]}

Castaldi, Christopher ^{[8
]}

Heltke, Jaime ^{[8
]}

Ng, Evelyn ^{[8
]}

Wheeler, John ^{[8
]}

Alfajaro, Mia Madel ^{[1
,9
]}

Levavasseur, Etienne ^{[5
]}

Fontes, Benjamin ^{[10
]}

Ravindra, Neal G. ^{[11
,12
]}

Van Dijk, David ^{[11
,12
]}

Mane, Shrikant ^{[2
,8
]}

Gunel, Murat ^{[2
,3
,13
]}

Ring, Aaron ^{[1
]}

Kazmi, Syed A. Jaffar ^{[14
]}

Zhang, Kai ^{[14
]}

Wilen, Craig B. ^{[1
,9
]}

Horvath, Tamas L. ^{[7
]}

Plu, Isabelle ^{[5
,16
]}

Haik, Stephane ^{[5
,10
,16
,17
]}

Thomas, Jean-Leon ^{[5
,18
]}

Louvi, Angeliki ^{[3
,13
]}

Farhadian, Shelli F. ^{[4
,18
]}

Huttner, Anita ^{[19
]}

Seilhean, Danielle ^{[5
,16
]}

Renier, Nicolas ^{[5
]}

Bilguvar, Kaya ^{[2
,8
]}

Iwasaki, Akiko ^{[1
,15
,20
]}

机构：

[1] Yale Sch Med, Dept Immunobiol, New Haven, CT 06510 USA

[2] Yale Sch Med, Dept Genet, New Haven, CT 06510 USA

[3] Yale Sch Med, Dept Neurosci, New Haven, CT USA

[4] Yale Sch Med, Dept Internal Med, Sect Infect Dis, New Haven, CT USA

[5] Sorbonne Univ, Paris Brain Inst, Inst Cerveau & Moelle Epiniere,INSERM, French Natl Ctr Sci Res,Joint Res Unit 7225,U1127, Paris, France

[6] Yale Univ, Dept Biomed Engn, New Haven, CT USA

[7] Yale Sch Med, Dept Comparat Med, New Haven, CT USA

[8] Yale Ctr Genome Anal, West Haven, CT 06510 USA

[9] Yale Sch Med, Dept Lab Med, New Haven, CT USA

[10] Yale Univ, Yale Environm Hlth & Safety, New Haven, CT USA

[11] Yale Sch Med, Cardiovasc Res Ctr, Dept Internal Med, Sect Cardiovasc Med, New Haven, CT USA

[12] Yale Univ, Dept Comp Sci, POB 2158, New Haven, CT 06520 USA

[13] Yale Sch Med, Dept Neurosurg, New Haven, CT USA

[14] Geisinger Med Ctr, Dept Lab Med, Danville, PA 17822 USA

[15] Yale Sch Med, Dept Mol Cellular & Dev Biol, New Haven, CT 06510 USA

[16] Hop La Pitie Salpetriere, AP HP, Dept Neuropathol, Paris, France

[17] Hop La Pitie Salpetriere, AP HP, Cellule Natl Reference Malad Creutzfeldt Jakob, Paris, France

[18] Yale Sch Med, Dept Neurol, New Haven, CT USA

[19] Yale Sch Med, Dept Pathol, New Haven, CT USA

[20] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2021年 / 218卷 / 03期

基金：

美国国家卫生研究院;

关键词：

HUMAN-SPECIFIC FEATURES; CEREBRAL ORGANOIDS; INFECTION; CELLS;

D O I：

10.1084/jem.20202135

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus on the consequences of CNS infections. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in infected and neighboring neurons. However, no evidence for type I interferon responses was detected. We demonstrate that neuronal infection can be prevented by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate SARS-CoV-2 neuroinvasion in vivo. Finally, in autopsies from patients who died of COVID-19, we detect SARS-CoV-2 in cortical neurons and note pathological features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV-2 and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

引用

页数：25

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