Analysis of the Host Transcriptome from Demyelinating Spinal Cord of Murine Coronavirus-Infected Mice

Abstract

Persistent infection of the mouse central nervous system (CNS) with mouse hepatitis virus (MHV) induces a demyelinating disease pathologically similar to multiple sclerosis and is therefore used as a model system. There is little information regarding the host factors that correlate with and contribute to MHV-induced demyelination. Here, we detail the genes and pathways associated with MHV-induced demyelinating disease in the spinal cord. High-throughput sequencing of the host transcriptome revealed that demyelination is accompanied by numerous transcriptional changes indicative of immune infiltration as well as changes in the cytokine milieu and lipid metabolism. We found evidence that a Th1-biased cytokine/chemokine response and eicosanoid-derived inflammation accompany persistent MHV infection and that antigen presentation is ongoing. Interestingly, increased expression of genes involved in lipid transport, processing, and catabolism, including some with known roles in neurodegenerative diseases, coincided with demyelination. Lastly, expression of several genes involved in osteoclast or bone-resident macrophage function, most notably TREM2 and DAP12, was upregulated in persistently infected mouse spinal cord. This study highlights the complexity of the host antiviral response, which accompany MHV-induced demyelination, and further supports previous findings that MHV-induced demyelination is immune-mediated. Interestingly, these data suggest a parallel between bone reabsorption by osteoclasts and myelin debris clearance by microglia in the bone and the CNS, respectively. To our knowledge, this is the first report of using an RNA-seq approach to study the host CNS response to persistent viral infection.

Demyelinating strain of mouse hepatitis virus infection bridging innate and adaptive immune response in the induction of demyelination

“…Four week old C57BL/6 mice were inoculated intracranially with DM (RSA59) or NDM (RSMHV2) strains using the LD 50 as described in prior studies [10][11][12]. To confirm infection, histopathology and immunohistochemistry were performed on liver, brain and spinal cord sections from mice whose spinal cords were processed for Microarray analysis.…”

“…Our recent studies using Affymetrix microarray analysis revealed that RSA59 induces IFN-gamma inducible genes and innate immune-activating pathway genes during the acute stage of infection [9]. Recent studies using a high-throughput RNA-Seq approach also revealed expression of several genes involved in macrophage function, immune infiltration, and changes in cytokine expression levels in response to persistent MHV infection in mice [10].…”

Protective Microglial Subset in Development, Aging, and Disease: Lessons From Transcriptomic Studies

“…Additionally, it was reported that microglial necroptosis in circumstances of lysophosphatidylcholine demyelination leads to repopulation by pro-regenerative CD11c+ microglia, as blocking of this mechanism prevented remyelination (148). Of note, demyelination induced by mouse hepatitis virus also led to enrichment of CD11c+ microglial gene signature in the spinal cord (149).…”

Cytoplasmic poly(A) binding protein-1 binds to genomically encoded sequences within mammalian mRNAs

“…mRNA-seq was performed as previously described (Elliott et al 2013). Briefly, total RNA was purified from the MEL cell cultures (miRNeasy; Qiagen).…”