Abstract
Intracranial (i.c.) infection of susceptible C57BL/6 mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) (a member of the Coronaviridae family) results in acute encephalomyelitis and viral persistence associated with an immune-mediated demyelinating disease. The present study was undertaken to better understand the molecular pathways evoked during innate and adaptive immune responses as well as the chronic demyelinating stage of disease in response to JHMV infection of the central nervous system (CNS). Using single-cell RNA sequencing analysis (scRNAseq) on flow-sorted CD45-positive (CD45+) cells enriched from brains and spinal cords of experimental mice, we demonstrate the heterogeneity of the immune response as determined by the presence of unique molecular signatures and pathways involved in effective antiviral host defense. Furthermore, we identify potential genes involved in contributing to demyelination as well as remyelination being expressed by both microglia and macrophages. Collectively, these findings emphasize the diversity of the immune responses and molecular networks at defined stages following viral infection of the CNS.IMPORTANCE Understanding the immunological mechanisms contributing to both host defense and disease following viral infection of the CNS is of critical importance given the increasing number of viruses that are capable of infecting and replicating within the nervous system. With this in mind, the present study was undertaken to evaluate the molecular signatures of immune cells within the CNS at defined times following infection with a neuroadapted murine coronavirus using scRNAseq. This approach has revealed that the immunological landscape is diverse, with numerous immune cell subsets expressing distinct mRNA expression profiles that are, in part, dictated by the stage of infection. In addition, these findings reveal new insight into cellular pathways contributing to control of viral replication as well as to neurologic disease.
Highlights
Intracranial infection of susceptible mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) provides an excellent model in which to interrogate molecular and cellular mechanisms of host defense and disease in response to viral infection of the central nervous system (CNS) [1, 2]
Histological features associated with viral persistence include the development of an immune-mediated demyelinating disease that is similar to the human demyelinating disease multiple sclerosis (MS), with infiltrating T cells and macrophages amplifying white matter damage [8, 17, 25]
We employed single-cell RNA sequencing on enriched CD45-positive (CD45ϩ) cells isolated from brains and spinal cords at defined times following JHMV infection to delineate mechanisms associated with effective host responses as well as those that contribute to both demyelination and remyelination within the CNS
Summary
Intracranial infection of susceptible mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) provides an excellent model in which to interrogate molecular and cellular mechanisms of host defense and disease in response to viral infection of the central nervous system (CNS) [1, 2]. Virus-specific CD4-positive (CD4ϩ) and CD8ϩ T cells infiltrate the CNS and control JHMV replication through gamma interferon (IFN-␥) secretion and perforin-mediated cytolytic activity [21, 22]. A robust cell-mediated immune response occurs during acute disease, sterilizing immunity is not achieved, resulting in viral persistence in white matter tracts [23]. The previous studies on bulk cell populations revealed important information on the mechanisms of disease and host defense in JHMV-infected mice, characterization of molecular alterations at the single-cell level is lacking. We employed single-cell RNA sequencing (scRNAseq) on enriched CD45-positive (CD45ϩ) cells isolated from brains and spinal cords at defined times following JHMV infection to delineate mechanisms associated with effective host responses as well as those that contribute to both demyelination and remyelination within the CNS
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