SARS-CoV-2 promotes microglial synapse elimination in human brain organoids

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Abstract

Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection initiate neuronal cell death and cause a loss of post-synaptic termini. Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure. We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synapse engulfment. To a large extent, SARS-CoV-2 exposed microglia adopt a transcriptomic profile overlapping with neurodegenerative disorders that display an early synapse loss as well as an increased incident risk after a SARS-CoV-2 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from COVID-19.

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Neurotoxic reactive astrocytes are induced by activated microglia

Shane Liddelow, Kevin A. Guttenplan, Laura Clarke … (2017)

A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.

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A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.

Hadas Keren‐Shaul, Amit Spinrad, Assaf Weiner … (2017)

Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)(-/-) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.

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Florent Ginhoux, Melanie Greter, Marylène Leboeuf … (2010)

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Author and article information

Contributors

Carl M. Sellgren:

ORCID: http://orcid.org/0000-0001-9103-2785

carl.sellgren@ki.se

Journal

Journal ID (nlm-ta): Mol Psychiatry

Journal ID (iso-abbrev): Mol Psychiatry

Title: Molecular Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 1359-4184

ISSN (Electronic): 1476-5578

Publication date (Electronic): 5 October 2022

Publication date PMC-release: 5 October 2022

Pages: 1-12

Affiliations

[1 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Physiology and Pharmacology, , Karolinska Institute, ; Stockholm, Sweden

[2 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Microbiology, Tumor and Cell Biology, , Karolinska Institute, ; Stockholm, Sweden

[3 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, , Karolinska University Hospital, ; Stockholm, Sweden

[4 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Center for Genomic Medicine and Department of Psychiatry, , Massachusetts General Hospital, ; Boston, MA USA

[5 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm County Council, , Karolinska University Hospital, ; Stockholm, Sweden

Author information

Martin Schalling http://orcid.org/0000-0001-5011-2922

Steven D. Sheridan http://orcid.org/0000-0003-1045-1158

Antonio G. Rothfuchs http://orcid.org/0000-0001-6001-7240

Carl M. Sellgren http://orcid.org/0000-0001-9103-2785

Article

Publisher ID: 1786

DOI: 10.1038/s41380-022-01786-2

PMC ID: 9533278

PubMed ID: 36198765

SO-VID: a50d287e-bc59-462c-af6b-7d20a6969c13

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 4 March 2022

Date revision received : 2 September 2022

Date accepted : 8 September 2022

Funding

Funded by: FundRef https://doi.org/10.13039/501100001862, Svenska Forskningsrådet Formas (Swedish Research Council Formas);

Award ID: 2017-02559

Award Recipient : Carl M. Sellgren

Funded by: FundRef https://doi.org/10.13039/501100004047, Karolinska Institutet (Karolinska Institute);

SARS-CoV-2 promotes microglial synapse elimination in human brain organoids

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Novel Coronavirus Disease COVID-19

Most cited references 53

Neurotoxic reactive astrocytes are induced by activated microglia

A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.

Fate mapping analysis reveals that adult microglia derive from primitive macrophages.

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