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Microglia Do Not Restrict SARS-CoV-2 Replication following Infection of the Central Nervous System of K18-Human ACE2 Transgenic Mice.
Olivarria, Gema M; Cheng, Yuting; Furman, Susana; Pachow, Collin; Hohsfield, Lindsay A; Smith-Geater, Charlene; Miramontes, Ricardo; Wu, Jie; Burns, Mara S; Tsourmas, Kate I; Stocksdale, Jennifer; Manlapaz, Cynthia; Yong, William H; Teijaro, John; Edwards, Robert; Green, Kim N; Thompson, Leslie M; Lane, Thomas E.
  • Olivarria GM; Department of Neurobiology and Behavior, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Cheng Y; Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Furman S; Department of Neurobiology and Behavior, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Pachow C; Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Hohsfield LA; Department of Neurobiology and Behavior, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Smith-Geater C; Department of Psychiatry and Human Behavior, University of California, Irvinegrid.266093.8 School of Medicine, Irvine, California, USA.
  • Miramontes R; Institute for Memory Impairments and Neurological Disorders, School of Biological Sciences, University of Californiagrid.266093.8, Irvine, Irvine, California, USA.
  • Wu J; Department of Biological Chemistry, University of California, Irvinegrid.266093.8 School of Medicine, Irvine, California, USA.
  • Burns MS; Department of Neurobiology and Behavior, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Tsourmas KI; Department of Neurobiology and Behavior, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Stocksdale J; Department of Neurobiology and Behavior, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Manlapaz C; Department of Neurobiology and Behavior, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Yong WH; Department of Pathology & Laboratory Medicine, University of California, Irvinegrid.266093.8 School of Medicine, Irvine, California, USA.
  • Teijaro J; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla California, USA.
  • Edwards R; Department of Pathology & Laboratory Medicine, University of California, Irvinegrid.266093.8 School of Medicine, Irvine, California, USA.
  • Green KN; Department of Neurobiology and Behavior, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Thompson LM; Department of Neurobiology and Behavior, University of California, Irvinegrid.266093.8, Irvine, California, USA.
  • Lane TE; Department of Psychiatry and Human Behavior, University of California, Irvinegrid.266093.8 School of Medicine, Irvine, California, USA.
J Virol ; 96(4): e0196921, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1702819
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 antiviral 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Virus Replication / Microglia / Central Nervous System Viral Diseases / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Virol Year: 2022 Document Type: Article Affiliation country: Jvi.01969-21

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Virus Replication / Microglia / Central Nervous System Viral Diseases / Angiotensin-Converting Enzyme 2 / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: J Virol Year: 2022 Document Type: Article Affiliation country: Jvi.01969-21