Abstract
Despite being vaccine preventable, rabies (lyssavirus) still has a significant impact on global mortality, disproportionally affecting children under 15 years of age. This neurotropic virus is deft at avoiding the immune system while travelling through neurons to the brain. Until recently, research efforts into the role of non-coding RNAs in rabies pathogenicity and detection have been hampered by a lack of human in vitro neuronal models. Here, we utilized our previously described human stem cell-derived neural model to investigate the effect of lyssavirus infection on microRNA (miRNA) expression in human neural cells and their secreted exosomes. Conventional differential expression analysis identified 25 cellular and 16 exosomal miRNAs that were significantly altered (FDR adjusted P-value <0.05) in response to different lyssavirus strains. Supervised machine learning algorithms determined 6 cellular miRNAs (miR-99b-5p, miR-346, miR-5701, miR-138-2-3p, miR-651-5p, and miR-7977) were indicative of lyssavirus infection (100% accuracy), with the first four miRNAs having previously established roles in neuronal function, or panic and impulsivity-related behaviors. Another 4-miRNA signatures in exosomes (miR-25-3p, miR-26b-5p, miR-218-5p, miR-598-3p) can independently predict lyssavirus infected cells with >99% accuracy. Identification of these robust lyssavirus miRNA signatures offers further insight into neural lineage responses to infection and provides a foundation for utilizing exosome miRNAs in the development of next-generation molecular diagnostics for rabies.
Highlights
Rabies virus (Family Rhabdoviridae, genus Lyssavirus) is among the most lethal viruses that invade and infect the central nervous system (CNS), leading to an estimated 59,000 deaths annually worldwide (Knobel et al, 2005; Schnell et al, 2010; Hampson et al, 2015; Olugasa et al, 2020; Abdulmoghni et al, 2021)
A lack of appropriate ex-vivo models for studying rabies infection in human neurons has contributed to the critical knowledge gap around the clinical pathogenesis of the virus
Despite recent advances in modelling neurotropic viruses in human neural stem cell systems (Tabari et al, 2020), the application of in vitro or human neural stem cell model systems has not been employed for improved differentiation between cellular or non-cellular miRNAs for lyssaviruses
Summary
Rabies virus (Family Rhabdoviridae, genus Lyssavirus) is among the most lethal viruses that invade and infect the central nervous system (CNS), leading to an estimated 59,000 deaths annually worldwide (Knobel et al, 2005; Schnell et al, 2010; Hampson et al, 2015; Olugasa et al, 2020; Abdulmoghni et al, 2021). The virus migrates to the brain via the peripheral nervous system in an asymptomatic pre-clinical phase, typically taking between two weeks and three months to occur (Schnell et al, 2010). More contemporary review of these methods has cast doubt on scientifically proven validity of this approach (Wilde and Hemachudha, 2015; Zeiler and Jackson, 2016)
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