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 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.

Promoting remyelination through cell transplantation therapies in a model of viral-induced neurodegenerative disease.

Multiple sclerosis (MS) is a central nervous system (CNS) disease characterized by chronic neuroinflammation, demyelination, and axonal damage. Infiltration of activated lymphocytes and myeloid cells are thought to be primarily responsible for white matter damage and axonopathy. Several United States Food and Drug Administration-approved therapies exist that impede activated lymphocytes from entering the CNS thereby limiting new lesion formation in patients with relapse-remitting forms of MS. However, a significant challenge within the field of MS research is to develop effective and sustained therapies that allow for axonal protection and remyelination. In recent years, there has been increasing evidence that some kinds of stem cells and their derivatives seem to be able to mute neuroinflammation as well as promote remyelination and axonal integrity. Intracranial infection of mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in immune-mediated demyelination and axonopathy, making this an excellent model to interrogate the therapeutic potential of stem cell derivatives in evoking remyelination. This review provides a succinct overview of our recent findings using intraspinal injection of mouse CNS neural progenitor cells and human neural precursors into JHMV-infected mice. JHMV-infected mice receiving these cells display extensive remyelination associated with axonal sparing. In addition, we discuss possible mechanisms associated with sustained clinical recovery. Developmental Dynamics 248:43-52, 2019. © 2018 Wiley Periodicals, Inc.

Neural precursor cells derived from induced pluripotent stem cells exhibit reduced susceptibility to infection with a neurotropic coronavirus.

The present study examines the susceptibility of mouse induced pluripotent stem cell-derived neural precursor cells (iPSC-NPCs) to infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). Similar to NPCs derived from striatum of day 1 postnatal GFP-transgenic mice (GFP-NPCs), iPSC-derived NPCs (iPSC-NPCs) are able to differentiate into terminal neural cell types and express MHC class I and II in response to IFN-γ treatment. However, in contrast to postnatally-derived NPCs, iPSC-NPCs express low levels of carcinoembryonic antigen-cell adhesion molecule 1a (CEACAM1a), the surface receptor for JHMV, and are less susceptible to infection and virus-induced cytopathic effects. The relevance of this in terms of therapeutic application of NPCs resistant to viral infection is discussed.