Differential Expression and Significance of Circulating microRNAs in Cerebrospinal Fluid of Acute Encephalitis Patients Infected with Japanese Encephalitis Virus

Abstract

Changes in circulating microRNAs (miRNAs) in the cerebrospinal fluid (CSF) have been associated with different neurological diseases. Here, we presented results of a pilot study aimed at determining the feasibility of detecting miRNAs in the CSF of Japanese Encephalitis virus (JEV) infected individuals with acute encephalitis syndrome (AES). We demonstrated the circulating miRNA profile in CSF of acute encephalitis patients infected with JEV. Using a quantitative real-time PCR-based miRNA array, we examined the level of 87 miRNAs expressed in human exosomes isolated from CSF. Subsequently, correlation between cytokine level and miRNAs expression in CSF samples was examined. In this study, we identified and validated the upregulated expression of three miRNAs, miR-21-5p, miR-150-5p, and miR-342-3p that were specifically circulated in CSF of acute encephalitis patients infected with JEV. CSF miR-21-5p, miR-150-5p, and miR-342-3p expressions were also elevated in infected mice brain. However, the expression pattern of these miRNAs differed in neuronal cells, microglial cells, and the exosome derived from JEV-infected cell culture supernatant. Interestingly, neuronal cells infected with vaccine strain (SA-14-14) did not lead to any upregulation of these three miRNAs. Further, miR-150-5p expression was found to be negatively correlated(r = -0.5279, p = 0.016) with TNFα level. Pathway analysis of putative target genes of these miRNAs indicated involvement of TGF-β, NGF, axon guidance, and MAPK signaling pathways in JEV/AES patients. This study for the first time represents the circulating miRNA in CSF of AES patients and identified the upregulated miRNAs in JEV-infected patients and offers the basis for future investigation.

Exosomal microRNA profiles from serum and cerebrospinal fluid in neurosyphilis

“…In a study investigating brain glioblastoma, miR-21-5p has been highly expressed 19. Moreover, a high expression in CSF in patients infected with Japanese encephalitis virus was detected 12. Similarly, in our study, we found that the expression of miR-21-5p was upregulated in the CSF of patients with neurosyphilis, which confirms that miR-21-5p is an miRNA closely related to CNS tumours and inflammation.…”

Exploitation of microRNAs by Japanese Encephalitis virus in human microglial cells

“…Consequently, the previous and current study indicates that these microRNAs might be relevant to JEV infection in human microglial cells. [36][37][38] Moreover, there are two pairs of microRNA and gene targets, which were consistent with the previous report. 13,39 Nevertheless, there are several other differentially expressed microRNAs, which have not been reported earlier in case of JEV infection in microglia, and might be novel to JEV infection.…”

“…In addition, several of the differentially expressed microRNAs were found common to the previous published reports for example, miR‐21, miR‐101‐3p, miR‐32‐5p, miR‐4695‐3p, miR‐432‐5p, miR‐205, miR‐450b‐3p, miR‐3613‐5p, miR‐190a, miR‐299‐5p, miR‐4286,miR‐1264, miR‐193a‐3p, miR‐138, miR‐3182, miR‐19a, miR‐1260b, miR‐3074, miR‐374b, miR‐588, miR‐597, miR‐487b, miR‐676, miR‐196a, miR‐539‐3p, miR‐802, miR‐629‐3p,miR‐301a‐3p, miR‐3156, miR‐222‐5p, and miR‐29b‐3p. Consequently, the previous and current study indicates that these microRNAs might be relevant to JEV infection in human microglial cells . Moreover, there are two pairs of microRNA and gene targets, which were consistent with the previous report .…”

Recent advances in Japanese encephalitis

“…The genes or pathways affected by these are being worked out; some of them are pathways in cancer, the neurotrophin signaling pathway, the Toll-like receptor signaling pathway, the Notch signaling pathways, and the JAK-STAT signaling pathway. In exosomes isolated from cerebrospinal fluid of JEV-infected human subjects, miR-21-5p, miR-150-5p, and miR-342-3p levels were found to be elevated, a trend that is also observed in infected mice brain 31 . Bioinformatic analysis for putative target genes of these three miRNAs indicated the involvement of transforming growth factor-beta (TGF-β), nerve growth factor (NGF), axon guidance, and mitogen-activated protein kinase (MAPK) signaling pathways 31 .…”

“…In exosomes isolated from cerebrospinal fluid of JEV-infected human subjects, miR-21-5p, miR-150-5p, and miR-342-3p levels were found to be elevated, a trend that is also observed in infected mice brain 31 . Bioinformatic analysis for putative target genes of these three miRNAs indicated the involvement of transforming growth factor-beta (TGF-β), nerve growth factor (NGF), axon guidance, and mitogen-activated protein kinase (MAPK) signaling pathways 31 . Thus, a vista of novel information has begun to be available that would help in better understanding the molecular pathology of JE and hopefully also in developing newer therapeutic interventions.…”