Role of Non-Coding RNA in Neurological Complications Associated With Enterovirus 71

Yang, Feixiang; Zhang, Ning; Chen, Yuxin; Yin, Jiancai; Xu, Muchen; Cheng, Xiang; Ma, Rujiang; Meng, Jialin; Du, Yan

doi:10.3389/fcimb.2022.873304

Cited by 7 publications

(4 citation statements)

References 188 publications

(224 reference statements)

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“…However, certain neurological complications such as encephalomyelitis, brainstem encephalitis, and aseptic meningitis ( Gonzalez et al,2019 ) can rapidly lead to neurogenic pulmonary edema ( Wang et al,2019 ) and, in severe cases, even death. Enterovirus type 71 (EV71)is the most common viral culprit behind these severe complications ( Yang et al, 2022 ). Currently, no clinically effective drugs exist, and symptomatic treatment remains the primary approach ( Liu et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Network pharmacology-based exploration identified the antiviral efficacy of Quercetin isolated from mulberry leaves against enterovirus 71 via the NF-κB signaling pathway

Liu,

Li,

Wang

et al. 2023

Front. Pharmacol.

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Introduction: Mulberry leaf (ML) is known for its antibacterial and anti-inflammatory properties, historically documented in “Shen Nong’s Materia Medica”. This study aimed to investigate the effects of ML on enterovirus 71 (EV71) using network pharmacology, molecular docking, and in vitro experiments.Methods: We successfully pinpointed shared targets between mulberry leaves (ML) and the EV71 virus by leveraging online databases. Our investigation delved into the interaction among these identified targets, leading to the identification of pivotal components within ML that possess potent anti-EV71 properties. The ability of these components to bind to the targets was verified by molecular docking. Moreover, bioinformatics predictions were used to identify the signaling pathways involved. Finally, the mechanism behind its anti-EV71 action was confirmed through in vitro experiments.Results: Our investigation uncovered 25 active components in ML that targeted 231 specific genes. Of these genes, 29 correlated with the targets of EV71. Quercetin, a major ingredient in ML, was associated with 25 of these genes. According to the molecular docking results, Quercetin has a high binding affinity to the targets of ML and EV71. According to the KEGG pathway analysis, the antiviral effect of Quercetin against EV71 was found to be closely related to the NF-κB signaling pathway. The results of immunofluorescence and Western blotting showed that Quercetin significantly reduced the expression levels of VP1, TNF-α, and IL-1β in EV71-infected human rhabdomyosarcoma cells. The phosphorylation level of NF-κB p65 was reduced, and the activation of NF-κB signaling pathway was suppressed by Quercetin. Furthermore, our results showed that Quercetin downregulated the expression of JNK, ERK, and p38 and their phosphorylation levels due to EV71 infection.Conclusion: With these findings in mind, we can conclude that inhibiting the NF-κB signaling pathway is a critical mechanism through which Quercetin exerts its anti-EV71 effectiveness.

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Section: Introductionmentioning

confidence: 99%

Network pharmacology-based exploration identified the antiviral efficacy of Quercetin isolated from mulberry leaves against enterovirus 71 via the NF-κB signaling pathway

Liu,

Li,

Wang

et al. 2023

Front. Pharmacol.

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“…HFMD, a childhood viral disease initiated by enteroviruses (EVs), can lead to aseptic meningitis, acute flaccid paralysis, and even neurogenic pulmonary edema ( Yang et al., 2022 ). However, there is little research regarding the effects of HFMD on eyes.…”

Section: Discussionmentioning

confidence: 99%

Enterovirus A71 infection-induced dry eye-like symptoms by damaging the lacrimal glands

Zhou,

Chen,

You

et al. 2024

Front. Cell. Infect. Microbiol.

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PurposeTo determine the effects of EV-A71 (Enterovirus A71) infection on ocular surface and its mechanism.MethodsAG6 mice aged two to three weeks were randomly divided into control and EV-A71 infected groups. Slit-lamp observation, fluorescein staining, and phenol red thread test were used to assess symptoms of ocular surface at 4 dpi (days post infection). The pathological changes of cornea and lacrimal gland were observed by H&E staining, PAS staining, TUNEL assay, IHC staining and qRT-PCR. Corneas and lacrimal glands from mice were obtained and processed for RNA sequencing analysis. Newly diagnosed HFMD patients caused by EV-A71 were recruited and ensured they met the inclusion criteria. Ocular surface parameters (TMH and NIKBUT) were measured using the OCULUS Keratograph 5M. Tear samples were taken to examine Cxcl1 and IL-6 levels through the ELISA method.ResultsMice studies revealed that EV-A71 infection caused tear film instability, decreased tear secretions, decreased in lacrimal gland size, and distinct goblet cell loss. It also resulted in increased large vacuoles within acinar cells and structural damage in lacrimal gland. Apart from minor damage to the epidermis, there was no obvious inflammatory changes or apoptosis in the cornea. However, there were significant inflammatory injury and apoptosis in the lacrimal gland. RNA-seq analysis showed IL-17 and NF-κB signaling pathways were activated in the lacrimal glands of mice infected with EV-A71. In HFMD patients, the THM was in a low range and NITBUT was significantly shorter than the control group by Oculus Keratograph 5M. ELISA assay showed a higher tear Cxcl1 and IL-6 level in them.ConclusionEV-A71 infection affected lacrimal gland structure and function and induced dry eye-like symptoms.

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“…It is classified as a member of the enterovirus genus within the Picornavirus family, possessing a positive single-stranded genome of approximately 7.4 kb in length. Currently, EV71 has become one of the main fatal viruses for those under 5 years old, with some severe complications in hand, foot, and mouth disease (HFMD), such as acute flaccid paralysis, brainstem encephalitis, neurological pulmonary edema, and even death ( 1 , 2 ). During the course of virus evolution, EV71 has employed numerous strategies to evade immune attack, thereby promoting its survival and replication ( 3 – 5 ).…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin E3 ligase SPOP is a host negative regulator of enterovirus 71-encoded 2A protease

Zang,

Yang,

Chen

et al. 2023

J Virol

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The 2A protease (2A pro ) encoded by enterovirus 71 (EV71) serves as an accessory protein with significant involvement in the regulation of EV71 infection and viral replication. EV71-2A pro exhibits the ability to suppress various host factors, thereby disrupting the cellular antiviral immune response. However, whether host factors downregulate EV71-2A pro remains largely unknown. Here, we discovered that the speckle-type POZ protein (SPOP), functioning as a host E3 ubiquitin ligase, triggers ubiquitination modifications and subsequent degradation of EV71-2A pro . SPOP interacts with EV71-2A pro and exhibits a dose-dependent downregulation of EV71-2A pro levels. Conversely, knockdown of endogenous SPOP upregulated EV71-2A pro levels. Subsequent investigations revealed that the SPOP facilitates the lysosome-dependent degradation of EV71-2A pro by inducing K48-linked polyubiquitination of EV71-2A pro , which ultimately restricts EV71 replication. These findings shed light on the ubiquitination and lysosome-dependent regulation of the crucial EV71-encoded protease, offering a potential therapeutic target for the treatment of EV71 infection. IMPORTANCE EV71 poses a significant health threat to children aged 5 and below. The process of EV71 infection and replication is predominantly influenced by ubiquitination modifications. Our previous findings indicate that EV71 prompts the activation of host deubiquitinating enzymes, thereby impeding the host interferon signaling pathway as a means of evading the immune response. Nevertheless, the precise mechanisms by which the host employs ubiquitination modifications to hinder EV71 infection remain unclear. The present study demonstrated that the nonstructural protein 2A pro , which is encoded by EV71, exhibits ubiquitination and degradation mediated by the host E3 ubiquitin ligase SPOP. In addition, it is the first report, to our knowledge, that SPOP is involved in the host antiviral response.

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Role of Non-Coding RNA in Neurological Complications Associated With Enterovirus 71

Cited by 7 publications

References 188 publications

Network pharmacology-based exploration identified the antiviral efficacy of Quercetin isolated from mulberry leaves against enterovirus 71 via the NF-κB signaling pathway

Network pharmacology-based exploration identified the antiviral efficacy of Quercetin isolated from mulberry leaves against enterovirus 71 via the NF-κB signaling pathway

Enterovirus A71 infection-induced dry eye-like symptoms by damaging the lacrimal glands

Ubiquitin E3 ligase SPOP is a host negative regulator of enterovirus 71-encoded 2A protease

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