Microglia Do Not Restrict SARS-CoV-2 Replication following Infection of the Central Nervous System of K18-Human ACE2 Transgenic Mice.

Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE

Publication: Washington Dc : American Society For Microbiology
Original Publication: Baltimore, American Society for Microbiology.

Angiotensin-Converting Enzyme 2/*immunology ; COVID-19/*immunology ; Central Nervous System Viral Diseases/*immunology ; Microglia/*immunology ; SARS-CoV-2/*physiology ; Virus Replication/*immunology; Angiotensin-Converting Enzyme 2/genetics ; Animals ; COVID-19/genetics ; Central Nervous System/immunology ; Central Nervous System/virology ; Central Nervous System Viral Diseases/genetics ; Central Nervous System Viral Diseases/virology ; Chemokines/genetics ; Chemokines/immunology ; Disease Models, Animal ; Humans ; Mice ; Mice, Transgenic ; Microglia/virology ; Neurons/immunology ; Neurons/virology ; Virus Replication/genetics

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.

Update of: bioRxiv. 2021 Nov 17;:. (PMID: 34816260)

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R01 NS083801 United States NS NINDS NIH HHS; 5T32AI060573 HHS | National Institutes of Health (NIH); P30CA062203 HHS | National Institutes of Health (NIH); R01NS083801 HHS | National Institutes of Health (NIH); CA-1607-25040 National Multiple Sclerosis Society (National MS Society); NS041249 HHS | National Institutes of Health (NIH); P30 CA062203 United States CA NCI NIH HHS; T32 AI060573 United States AI NIAID NIH HHS; T32 NS082174 United States NS NINDS NIH HHS; R35 NS116872 United States NS NINDS NIH HHS; R35 NS116835 United States NS NINDS NIH HHS; R01 NS041249 United States NS NINDS NIH HHS

Keywords: SARS-CoV-2; central nervous system; microglia; neuropathology

0 (Chemokines)
EC 3.4.17.23 (ACE2 protein, human)
EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)

Date Created: 20211222 Date Completed: 20220228 Latest Revision: 20230222

20240829

PMC8865461

10.1128/jvi.01969-21

34935438