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

ABSTRACT: 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 whether the virus can infect the brain, or what the consequences of CNS infection are. 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 the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2.

SUBMITTER: Song E

PROVIDER: S-EPMC7491522 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Song Eric E Zhang Ce C Israelow Benjamin B Lu-Culligan Alice A Prado Alba Vieites AV Skriabine Sophie S Lu Peiwen P Weizman Orr-El OE Liu Feimei F Dai Yile Y Szigeti-Buck Klara K Yasumoto Yuki Y Wang Guilin G Castaldi Christopher C Heltke Jaime J Ng Evelyn E Wheeler John J Alfajaro Mia Madel MM Levavasseur Etienne E Fontes Benjamin B Ravindra Neal G NG Van Dijk David D Mane Shrikant S Gunel Murat M Ring Aaron A Kazmi Syed A Jaffar SAJ Zhang Kai K Wilen Craig B CB Horvath Tamas L TL Plu Isabelle I Haik Stephane S Thomas Jean-Leon JL Louvi Angeliki A Farhadian Shelli F SF Huttner Anita A Seilhean Danielle D Renier Nicolas N Bilguvar Kaya K Iwasaki Akiko A

bioRxiv : the preprint server for biology 20200908

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 whether the virus can infect the brain, or what the consequences of CNS infection are. 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 the infected a ...[more]

PMID: 32935108

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Project description:BackgroundPeople with alcohol use disorder (AUD) may be at higher risk for COVID-19. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are required for cellular entry by SARS-CoV-2, but information on their expression in specific brain regions after alcohol exposure is limited. We sought to clarify how chronic alcohol exposure affects ACE2 expression in monoaminergic brainstem circuits and other putative SARS-CoV-2 entry points.MethodsBrains were examined for ACE2 using immunofluorescence after 4 weeks of chronic intermittent ethanol (CIE) vapor inhalation. We also examined TMPRSS2, Cathepsin L, and ADAM17 by Western blot and RAS pathway mediators and pro-inflammatory markers via RT-qPCR.ResultsACE2 was increased in most brain regions following CIE including the olfactory bulb (OB), hypothalamus (HT), raphe magnus (RMG), raphe obscurus (ROB), locus coeruleus (LC), and periaqueductal gray (PAG). We also observed increased colocalization of ACE2 with monoaminergic neurons in brainstem nuclei. Moreover, soluble ACE2 (sACE2) was elevated in OB, HT, and LC. The increase in sACE2 in OB and HT was accompanied by upregulation of ADAM17, an ACE2 sheddase, while TMPRSS2 increased in HT and LC. Cathepsin L, an endosomal receptor involved in viral entry, was also increased in OB. Alcohol can increase Angiotensin II, which triggers a pro-inflammatory response that may upregulate ACE2 via activation of RAS pathway receptors AT1R/AT2R. ACE2 then metabolizes Angiotensin II to Angiotensin (1-7) and provokes an anti-inflammatory response via MAS1. Accordingly, we report that AT1R/AT2R mRNA decreased in OB and increased in the LC, while MAS1 mRNA increased in both OB and LC. Other mRNAs for pro-inflammatory markers were also dysregulated in OB, HT, raphe, and LC.ConclusionsOur results suggest that alcohol triggers a compensatory upregulation of ACE2 in the brain due to disturbed RAS and may increase the risk or severity of SARS-CoV-2 infection.

Dataset Information

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

Publications

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

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