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Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18-hACE2 transgenic mice

Gema M. Olivarria, Yuting Cheng, Susana Furman, Collin Pachow, Lindsay A. Hohsfield, Charlene Smith-Geater, Ricardo Miramontes, Jie Wu, Mara S. Burns, Kate I. Tsourmas, Jennifer Stocksdale, Cynthia Manlapaz, William H. Yong, John Teijaro, View ORCID ProfileRobert Edwards, Kim N. Green, Leslie M. Thompson, View ORCID ProfileThomas E. Lane
doi: https://doi.org/10.1101/2021.11.15.468761
Gema M. Olivarria
1Department of Neurobiology & Behavior, School of Biological Sciences, University of California, Irvine 92697
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Yuting Cheng
2Department of Molecular Biology & Biochemistry, School of Biological Sciences, University of California, Irvine 92697
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Susana Furman
1Department of Neurobiology & Behavior, School of Biological Sciences, University of California, Irvine 92697
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Collin Pachow
2Department of Molecular Biology & Biochemistry, School of Biological Sciences, University of California, Irvine 92697
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Lindsay A. Hohsfield
1Department of Neurobiology & Behavior, School of Biological Sciences, University of California, Irvine 92697
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Charlene Smith-Geater
3Department of Psychiatry and Human Behavior, University of California, Irvine School of Medicine, Irvine 92697
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Ricardo Miramontes
4Institute for Memory Impairments and Neurological Disorders, School of Biological Sciences, University of California, Irvine 92697
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Jie Wu
5Department of Biological Chemistry, University of California, Irvine School of Medicine, Irvine 92697
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Mara S. Burns
1Department of Neurobiology & Behavior, School of Biological Sciences, University of California, Irvine 92697
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Kate I. Tsourmas
1Department of Neurobiology & Behavior, School of Biological Sciences, University of California, Irvine 92697
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Jennifer Stocksdale
1Department of Neurobiology & Behavior, School of Biological Sciences, University of California, Irvine 92697
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Cynthia Manlapaz
1Department of Neurobiology & Behavior, School of Biological Sciences, University of California, Irvine 92697
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William H. Yong
6Department of Pathology & Laboratory Medicine, University of California, Irvine School of Medicine, Irvine 92697
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John Teijaro
7Department of Immunology & Microbiology, The Scripps Research Institute, La Jolla CA 92037
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Robert Edwards
6Department of Pathology & Laboratory Medicine, University of California, Irvine School of Medicine, Irvine 92697
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Kim N. Green
1Department of Neurobiology & Behavior, School of Biological Sciences, University of California, Irvine 92697
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Leslie M. Thompson
1Department of Neurobiology & Behavior, School of Biological Sciences, University of California, Irvine 92697
3Department of Psychiatry and Human Behavior, University of California, Irvine School of Medicine, Irvine 92697
5Department of Biological Chemistry, University of California, Irvine School of Medicine, Irvine 92697
6Department of Pathology & Laboratory Medicine, University of California, Irvine School of Medicine, Irvine 92697
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Thomas E. Lane
1Department of Neurobiology & Behavior, School of Biological Sciences, University of California, Irvine 92697
2Department of Molecular Biology & Biochemistry, School of Biological Sciences, University of California, Irvine 92697
8Center for Virus Research, University of California, Irvine 92697
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  • For correspondence: tlane@uci.edu
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Abstract

Unlike SARS-CoV-1 and MERS-CoV, infection with SARS-CoV-2, the viral pathogen responsible for COVID-19, is often associated with neurologic symptoms that range from mild to severe, yet increasing evidence argues the virus does not exhibit extensive neuroinvasive properties. We demonstrate SARS-CoV-2 can infect and replicate in human iPSC-derived neurons and that infection shows limited anti-viral and inflammatory responses but increased activation of EIF2 signaling following infection as determined by RNA sequencing. Intranasal infection of K18 human ACE2 transgenic mice (K18-hACE2) with SARS-CoV-2 resulted in lung pathology associated with viral replication and immune cell infiltration. In addition, ∼50% of infected mice exhibited CNS infection characterized by wide-spread viral replication in neurons accompanied by increased expression of chemokine (Cxcl9, Cxcl10, Ccl2, Ccl5 and Ccl19) and cytokine (Ifn-λ and Tnf-α) transcripts associated with microgliosis and a neuroinflammatory response consisting primarily of monocytes/macrophages. Microglia depletion via administration of colony-stimulating factor 1 receptor inhibitor, PLX5622, in SARS-CoV-2 infected mice did not affect survival or viral replication but did result in dampened expression of proinflammatory cytokine/chemokine transcripts and a reduction in monocyte/macrophage infiltration. These results argue that microglia are dispensable in terms of controlling SARS-CoV-2 replication in in the K18-hACE2 model but do contribute to an inflammatory response through expression of pro-inflammatory genes. Collectively, these findings contribute to previous work demonstrating the ability of SARS-CoV-2 to infect neurons as well as emphasizing the potential use of the K18-hACE2 model to study immunological and neuropathological aspects related to SARS-CoV-2-induced neurologic disease.

Importance Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the role of microglia in aiding in host defense following experimental infection of the central nervous system (CNS) of K18-hACE2 with SARS-CoV-2, the causative agent of COVID-19. Neurologic symptoms that range in severity are common in COVID-19 patients and understanding immune responses that contribute to restricting neurologic disease can provide important insight into better understanding consequences associated with SARS-CoV-2 infection of the CNS.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 17, 2021.
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Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18-hACE2 transgenic mice
Gema M. Olivarria, Yuting Cheng, Susana Furman, Collin Pachow, Lindsay A. Hohsfield, Charlene Smith-Geater, Ricardo Miramontes, Jie Wu, Mara S. Burns, Kate I. Tsourmas, Jennifer Stocksdale, Cynthia Manlapaz, William H. Yong, John Teijaro, Robert Edwards, Kim N. Green, Leslie M. Thompson, Thomas E. Lane
bioRxiv 2021.11.15.468761; doi: https://doi.org/10.1101/2021.11.15.468761
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Microglia do not restrict SARS-CoV-2 replication following infection of the central nervous system of K18-hACE2 transgenic mice
Gema M. Olivarria, Yuting Cheng, Susana Furman, Collin Pachow, Lindsay A. Hohsfield, Charlene Smith-Geater, Ricardo Miramontes, Jie Wu, Mara S. Burns, Kate I. Tsourmas, Jennifer Stocksdale, Cynthia Manlapaz, William H. Yong, John Teijaro, Robert Edwards, Kim N. Green, Leslie M. Thompson, Thomas E. Lane
bioRxiv 2021.11.15.468761; doi: https://doi.org/10.1101/2021.11.15.468761

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