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Novel Model of Multiple Sclerosis Induced by EBV-like Virus Generates a Unique B Cell Population

ABSTRACT: Objective: Multiple sclerosis (MS) is a chronic, autoimmune disease of the central nervous system. Prior infection with Epstein-Barr virus (EBV), a gammaherpesvirus, is deemed a necessary yet insufficient factor in the development of MS. The objective of this study was to determine whether the EBV-like virus, murid gammaherpesvirus 68, is sufficient to induce inflammatory demyelinating disease in a transgenic TCR mouse strain susceptible to CNS autoimmunity. Methods: B10.PL mice that express the myelin basic protein-specific transgenic T cell receptor (TCRMBP) were intranasally inoculated with murid gammaherpesvirus 68 virus (MHV68), PR8 influenza virus, or PBS. Mice were evaluated for the development of neurologic deficits. Flow cytometry and fluorescent microscopy were used to validate the infiltration of immune cells in the brain and spinal cord of TCRMBP mice. Single cell RNA sequencing of splenic B cells was performed to determine transcriptional changes that resulted from MHV68 infection. Results: MHV68-infected mice developed neurological deficits at a significantly higher frequency (70.8%) than the influenza (7.7%) or mock-infected mice (13.3%). MHV68 infected mice exhibited signs including optic neuritis and ataxia, which are infrequently observed in EAE mice, but common in MS patients. MHV68-infected mice exhibited increased focal immune cell infiltration. Single cell RNA sequencing identified the emergence of a novel, MHV68 infection-associated population of memory-like B cells that highly express genes associated with antigen presentation and costimulation. Conclusion: Infecting myelin basic protein specific TCR transgenic mice with the EBV analogue, MHV68, generates encephalitogenic disease without myelin immunization. MHV68 drives a distinct transcriptional program in B cells capable of enhanced antigen presentation and costimulation to drive an autoreactive T cell response.

ORGANISM(S): Mus musculus

PROVIDER: GSE261605 | GEO | 2024/04/02

REPOSITORIES: GEO

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Project description:MicroRNA (miRNA) and endogenous siRNA (endo-siRNA) are two essential classes of small noncoding RNAs (sncRNAs) in eukaryotic organisms. The class of miRNA is diverse and there exist noncanonical miRNAs that bypass the canonical miRNA biogenesis pathway. In order to identify noncanonical miRNAs and endo-siRNAs responding to virus infection and study their potential function, we sequenced small-RNA species from cells lytically infected with murine gammaherpesvirus 68. In addition to 3 novel canonical miRNAs in mouse, two antisense miRNAs in virus and 25 novel noncanonical miRNAs, including miRNAs derived from tRNAs, snoRNAs and introns, in the host were identified. These noncanonical miRNAs exhibited features distinct from canonical miRNAs in the lengths and structures of miRNA hairpins as well as base pairings and first nucleotide preference. Many of the novel miRNAs are conserved in mammals. In addition to several known murine endo-siRNAs detected by the sequencing profiling, a novel locus in the mouse genome was identified to give rise to endo-siRNAs. This novel endo-siRNA locus is comprised of two tandem inverted B4 short interspersed nuclear elements (SINEs). Unexpectedly, the SINE-derived endo-siRNAs were found in a variety of sequencing data as well as virus-infected cells. Moreover, a murine miRNA was up-regulated more than 35 fold in infected than in mock-treated cells. The putative target genes of the viral and the up-regulated murine miRNAs were potentially involved in processes of gene transcription and protein phosphorylation and localized to membranes, suggesting their role in manipulating the host basal immune system during lytic infection. Our results extended the number of noncanonical miRNAs in mammals and shed new lights on their potential functions of lytic infection of MHV68. Mouse NIH 3T12 cells infectd with MHV68 (3 samples) and mock-treated (2 samples) were examined. Noncanonical microRNAs and endogenous siRNAs discovery in lytic infection of murine gammaherpesvirus MHV68 (NC_001826.2).

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Novel Model of Multiple Sclerosis Induced by EBV-like Virus Generates a Unique B Cell Population

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