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

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.

Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders?

“…In addition to the astroglial role in preventing CNS spreading of MHV-A59, microglia seem also to be required to control neurotropic CoV infection. A recently published article showed that depletion of microglia using PLX5622, an inhibitor of colony-stimulating factor 1 receptor (CSF1R), in animals exposed to JHM-MHV increased mortality, impaired control of viral replication, altered CD4+ and CD8+ T-cell infiltration, increased demyelination, and decreased neuro-repair ( Mangale et al., 2020 ).…”

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and glial cells: Insights and perspectives

“…2 ). On one hand, microglial cells act in the innate immune response in the CNS and are essential for restricting viral replication and activating proper systemic anti-viral responses ( Wheeler et al., 2018 ; Klein et al., 2019 ; Mangale et al., 2020 ). On the other hand, these cells can also have detrimental effects, indirectly by activating astrocyte-mediated neurotoxicity ( Tremblay et al., 2011 ) and directly by inducing synapse loss ( Klein et al., 2019 ; Trzeciak et al., 2019 ) ( Fig.…”

“…For example, in an in vivo murine model of infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV), microglial cells are necessary for effective restriction of viral replication in the CNS. Furthermore, microglial depletion disturbs the host systemic T cell anti-viral response and leads to increased neurological manifestations (demyelination), morbidity and mortality ( Wheeler et al., 2018 ; Mangale et al., 2020 ).…”

“…As shown by these studies, microglial cells are important not only for the intrinsic anti-viral response in the CNS tissue but also as powerful activators of the systemic anti-viral immunity in the case of neurotrophic coronavirus ( Wheeler et al., 2018 ; Mangale et al., 2020 ). In this sense, in vivo microglial cell interactions with the immune system and with the microbiota have proven to be important in an effective anti-viral response, both on the systemic level and at the CNS ( Brown et al., 2019 ).…”

“…Furthermore, the crosstalk between microglial cells and the immune system outside of the CNS involves several steps, from the recruitment and activation of peripheral monocytes/macrophages to enhancement of the innate immune response ( Templeton et al., 2008 ; Fekete et al., 2018 ) and to the activity of antigen presenting cells (APCs) and cytokine producers activating both APCs in the periphery and viral-specific T cells and controlling viral spread ( Suzumura et al., 1988 ; Malone et al., 2006 ; Zimmermann et al., 2017 ; Wheeler et al., 2018 ; Brown et al., 2019 ; Mangale et al., 2020 ). Also, systemic responses are important to clear infected APC-like microglial cells ( Herz et al., 2015 ).…”