Abstract
Japanese encephalitis virus (JEV), the leading cause of viral encephalitis in Asia, is neurovirulent and neuroinvasive. Neurons are the main target of JEV infection and propagation. Receptor interacting serine/threonine-protein kinase 3 (RIPK3) has been reported to contribute to neuroinflammation and neuronal death in many central nervous system diseases. In this study, we found that the progression of JE was alleviated in RIPK3-knockout (RIPK3–/–) mice in both peripheral and intracerebral infection. RIPK3-knockdown (RIPK3-RNAi) neuro2a cells showed higher cell viability during JEV infection. Moreover, the JEV load was significantly decreased in RIPK3–/– mouse-derived primary neurons and RIPK3-RNAi neuro2a cells compared with wild-type neurons, but this was not observed in microglia. Furthermore, RNA sequencing of brain tissues showed that the level of the interferon (IFN)-induced protein 44-like gene (IFI44L) was significantly increased in JEV-infected RIPK3–/– mouse brains, RIPK3–/– neurons, and RIPK3-RNAi-neuro2a cells. Then, it was demonstrated that the propagation of JEV was inhibited in IFI44L-overexpressing neuro2a cells and enhanced in IFI44L and RIPK3 double knockdown neuro2a cells. Taken together, our results showed that the increased expression of RIPK3 following JEV infection played complicated roles. On the one hand, RIPK3 participated in neuroinflammation and neuronal death during JEV infection. On the other hand, RIPK3 inhibited the expression of IFI44L to some extent, leading to the propagation of JEV in neurons, which might be a strategy for JEV to evade the cellular innate immune response.
Highlights
Japanese encephalitis virus (JEV) is a positive-sense, single-stranded RNA virus belonging to the genus Flavivirus in the family Flaviviridae
Pattern recognition receptors (PRRs), such as retinoic acidinducible gene 1-like receptors (RIG-I) and Toll-like receptor 3 (TLR3), in infected cells can recognize viral components and induce the production of interferons (IFNs), which drive the expression of various IFN-stimulated genes (ISGs) through the IFN receptor (IFNR)/Janus kinase (Jak1)/tyrosine kinase (Tyk)2/signal transducer and activator of transcription (STAT)1/STAT2 pathway to fight against virus invasion (Liu et al, 2013; Han et al, 2014)
The results showed that Receptor interacting serine/threonine-protein kinase 3 (RIPK3)−/− mice had an increased survival rate compared with WT mice after JEV infection (Figure 1A)
Summary
Japanese encephalitis virus (JEV) is a positive-sense, single-stranded RNA virus belonging to the genus Flavivirus in the family Flaviviridae. Receptor interacting serine/threonine-protein kinase 3 (RIPK3) has been shown to participate in several biological or pathological processes and play complicated and even controversial roles in different host cells during various viral infections (He and Wang, 2018). It has been reported that RIPK3-mediated necroptosis destroys host cells and limits the propagation of viruses such as herpes simplex virus (HSV), influenza virus (IAV), and vaccinia virus (VV) (Wang et al, 2014; Huang et al, 2015; Nogusa et al, 2016; Koehler et al, 2017). RIPK3 promoted or inhibited the propagation of virus in a cell death-independent manner during coxsackievirus B3 (CVB), IAV, and Zika virus (ZIKV) infections (Harris et al, 2015; Downey et al, 2017; Daniels et al, 2019). The role of RIPK3 in JEV infection is unknown
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