Comparative transcriptome profiling of the lumbosacral dorsal root ganglia reveals sexually dimorphic gene expression in a murine model of coronavirus-induced neurodegeneration.

Introduction: Neuroinflammation of the central nervous system (CNS) triggers long-lasting neurodegenerative changes associated with the development of neurogenic dysfunction in the pelvic organs. We previously described the symptoms of voiding dysfunction in a mouse model of multiple sclerosis (MS) induced by a coronaviral infection with mouse hepatitis virus (MHV). The aim of the current study was to identify immune, inflammatory and neuronal changes in the lumbosacral (L6-S2) dorsal root ganglia (DRG) innervating the lower urinary tract (LUT) after severe neurodegeneration in the CNS.

Methods: Adult C57BL/6 male (N=18) and female (N=18) mice received either an intracranial injection of MHV (coronavirus-induced encephalomyelitis, CIE group), or sterile saline (control group). Dorsal root ganglia were collected from mice of both sexes at 1 and 4 weeks, followed by isolation of total RNA and bulk RNA sequencing.

Results: Transcriptome analysis of LS DRG identified a sex dependent expression of the genes at baseline with females having an increased expression of the immune system and extracellular matrix (ECM) related differentially expressed genes (DEGs) whereas males showed an upregulation of the genes belonging to protein synthesis, folding, and post-translational phosphorylation. Acute neuroinflammation (1 wk post-infection) triggered extensive immune responses involving the families of interferons (Ifna2, Ifng, Ifnl1), interleukins (Il1a, Il1b, Il6), toll-like receptors (Tlr9, Tlr7), and guanylate-binding proteins (GTPases, Gbp) in both, CIE males and females. However, at a later stage of neurodegeneration (4 wks post-infection), the number of upregulated DEGs was down 6-fold in CIE males, whereas in CIE females the downregulated pathways were predominant, and mostly included genes encoding motor proteins (Myh7, Myl2, Myl3, Tnnt1, TnnI1, Dnah5). Among the pathways upregulated in males but downregulated in females at both time points were phagosome formation pathway, neutrophil extracellular trap signaling, and hepatic fibrosis pathway.

Conclusions: This study confirmed a differential expression of immune, inflammatory, and neural DEGs in sensory ganglia of male and female mice undergoing CNS neurodegeneration and neuroinflammation. The obtained results suggest a functional role of sex-dependent sensory interoception in the development of neurogenic LUTS in a coronavirus-induced murine model of MS.