Microglia influence host defense, disease, and repair following murine coronavirus infection of the central nervous system

The present study examines functional contributions of microglia in host defense, demyelination, and remyelination following infection of susceptible mice with a neurotropic coronavirus. Treatment with PLX5622, an inhibitor of colony stimulating factor 1 receptor (CSF1R) that efficiently depletes mi...

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Bibliographic Details
Published in:	Glia Vol. 68; no. 11; pp. 2345 - 2360
Main Authors:	Mangale, Vrushali, Syage, Amber R., Ekiz, H. Atakan, Skinner, Dominic D., Cheng, Yuting, Stone, Colleen L., Brown, R. Marshall, O'Connell, Ryan M., Green, Kim N., Lane, Thomas E.
Format:	Journal Article
Language:	English
Published:	Hoboken, USA John Wiley & Sons, Inc 01-11-2020 Wiley Subscription Services, Inc
Subjects:	Animals Apolipoprotein E Biomedical materials Brain - drug effects Brain - immunology Brain - virology CD4 antigen CD45 antigen CD86 antigen Cell activation Central nervous system Colony-stimulating factor Coronaviridae coronavirus Coronavirus Infections - chemically induced Coronavirus Infections - immunology Coronaviruses Cystatins Damage Demyelination Dendritic cells Gene sequencing Growth factors Hepatitis host defense Host-Pathogen Interactions - drug effects Host-Pathogen Interactions - immunology Immunity, Cellular - drug effects Immunity, Cellular - immunology Infections Insulin Insulin-like growth factor I Lipase Lipoprotein lipase Lymphocytes Lymphocytes T Macrophages Major histocompatibility complex Male Mice Mice, Inbred C57BL Microglia Microglia - drug effects Microglia - immunology Microglia - virology Murine hepatitis virus - immunology Myelination Myeloid cells Nervous system Nervous tissues Organic Chemicals - toxicity Osteopontin Receptors remyelination Repair Replication Ribonucleic acid RNA Spinal cord Substantia alba Viruses coronavirus microglia demyelination host defense remyelination
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Summary:	The present study examines functional contributions of microglia in host defense, demyelination, and remyelination following infection of susceptible mice with a neurotropic coronavirus. Treatment with PLX5622, an inhibitor of colony stimulating factor 1 receptor (CSF1R) that efficiently depletes microglia, prior to infection of the central nervous system (CNS) with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality compared with control mice that correlated with impaired control of viral replication. Single cell RNA sequencing (scRNASeq) of CD45+ cells isolated from the CNS revealed that PLX5622 treatment resulted in muted CD4+ T cell activation profile that was associated with decreased expression of transcripts encoding MHC class II and CD86 in macrophages but not dendritic cells. Evaluation of spinal cord demyelination revealed a marked increase in white matter damage in PLX5622‐treated mice that corresponded with elevated expression of transcripts encoding disease‐associated proteins Osteopontin (Spp1), Apolipoprotein E (Apoe), and Triggering receptor expressed on myeloid cells 2 (Trem2) that were enriched within macrophages. In addition, PLX5622 treatment dampened expression of Cystatin F (Cst7), Insulin growth factor 1 (Igf1), and lipoprotein lipase (Lpl) within macrophage populations which have been implicated in promoting repair of damaged nerve tissue and this was associated with impaired remyelination. Collectively, these findings argue that microglia tailor the CNS microenvironment to enhance control of coronavirus replication as well as dampen the severity of demyelination and influence repair. Main points Microglia augment host defense in response to CNS infection by the neurotropic coronavirus JHMV. A role for microglia in restricting demyelination and promoting remyelination in JHMV infected mice also is demonstrated.
Bibliography:	Funding information Vrushali Mangale, Amber R. Syage, and H. Atakan Ekiz equally contributed to this work National Institute of Neurological Disorders and Stroke, Grant/Award Numbers: R01NS041249, R01NS091939; National Institutes of Health, Grant/Award Number: R01AG047956; National Multiple Sclerosis Society, Grant/Award Number: CA‐1607‐25040 Funding information National Institute of Neurological Disorders and Stroke, Grant/Award Numbers: R01NS041249, R01NS091939; National Institutes of Health, Grant/Award Number: R01AG047956; National Multiple Sclerosis Society, Grant/Award Number: CA‐1607‐25040
ISSN:	0894-1491 1098-1136
DOI:	10.1002/glia.23844