Abstract
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.
Highlights
Intracranial inoculation of C57BL/6 mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV), a member of the Coronaviridae family, leads to an acute encephalomyelitis in which virus infects and replicates within glial cells with relative sparing of neurons (Bergmann, Lane, & Stohlman, 2006; Lane & Hosking, 2010; Templeton & Perlman, 2007; Weiss & Leibowitz, 2011)
The CD4+ T cells subset from PLX5622-treated mice expressed reduced transcripts for Il2ra (p < .05)and Il2rb (p < .01) that encode for components of the IL-2 receptor when compared to control-treated mice (Figure 4a)
Through scRNAseq analysis of CD45 + -enriched cells from the spinal cords of JHMV-infected mice treated with either PLX5622 or control chow, we consistently observed a dramatic increase in transcripts encoding for molecules associated with demyelination including Apoliprotein E (Apoe) (Krasemann et al, 2017), Osteopontin (Spp1) (Chabas et al, 2001), and Triggering receptor expressed on myeloid cells (Trem2) (Krasemann et al, 2017; Ulrich & Holtzman, 2016) in macrophage clusters within the spinal cords of PLX5622-treated mice compared to controls (Figure 7c)
Summary
Intracranial inoculation of C57BL/6 mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV), a member of the Coronaviridae family, leads to an acute encephalomyelitis in which virus infects and replicates within glial cells with relative sparing of neurons (Bergmann, Lane, & Stohlman, 2006; Lane & Hosking, 2010; Templeton & Perlman, 2007; Weiss & Leibowitz, 2011). While the functional roles of T cells and B cells in both host defense and disease in JHMV-infected mice have been extensively studied, there is increasing interest in better understanding how resident cells of the CNS contribute to these events. The functional role of microglia in contributing to host defense in response to CNS infection with neurotropic viruses has been examined These studies have been greatly aided by findings demonstrating that mice lacking colony stimulating factor 1 receptor (CSF1R−/−) lack microglia emphasizing the importance of this signaling pathway in microglia development (Ginhoux et al, 2010). Our findings emphasize an important role for microglia in aiding in host defense in response to JHMV infection of the CNS as well as influencing both the severity of spinal cord demyelination and remyelination in a model of murine coronavirus-induced neurologic disease
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