Gp78 regulates PMP22 and causes ER stress and autophagy in EV71-VP1-overexpressing mouse Schwann cells

Background:During Enterovirus type 71(EV71)infection,the structural viral protein 1(VP1)activates endoplasmic reticulum(ER)stress associated with peripheral myelin protein 22(PMP22)accumulation and induces autophagy.However,the specific mechanism behind this process remains elusive.Methods:In this research,we used the VP1-overexpressing mouse Schwann cells(SCs)models co-transfected with a PMP22 silencing or Autocrine motility factor receptor(AMFR/gp78)overexpressing vector to explore the regulation of gp78 on PMP22 and its relationship with autophagy and apoptosis.Results:The activity of gp78 could be influenced by EV71-VP1,leading to a decrease in the ubiquitination and degradation of PMP22,resulting in PMP22 accumulation in ER.In VP1-overexpressing mouse SCs,all three ER stress sensors,including pancreatic endoplasmic reticulum kinase(PERK),activating transcription factor 6(ATF6)and inositol-requiring enzyme 1(IRE1)and the related downstream signals(C/EBP-homologous protein(CHOP)and Caspase 12)were activated,as well as the ER-resident chaperone Glucose-regulated protein 78(GRP78).In addition,VP1 upregulated the autophagy marker Microtubule-associated protein 1 light chain 3 beta(LC3B),while PMP22 silencing or gp78 overexpression reversed the phenomenon.Meanwhile,PMP22 silencing or gp78 overexpression increased proliferation of EV71-VP1-transfected mouse SCs.Conclusion:Gp78 could regulate PMP22 accumulation through ubiquitination degradation and cause ER stress and autophagy in EV71-VP1-overexpressing mouse SCs.Therefore,the gp78/PMP22/ER stress axis might emerge as a promising therapeutic target for myelin and neuronal damage induced by EV71 infection.

Central Brain Herniation Secondary to Influenza-Related Encephalopathy in a Pontocerebellar Hypoplasia Child: A Case Report and Review

Influenza-associated encephalopathy (IAE) can perform as varying patterns of neuroimaging. Central brain herniation (CBH) secondary to IAE is rare;it may be a bad prognosis. Here, we presented a 4-year-old girl with influenza who had a pontocerebellar hypoplasia (PCH) history;she performed the second Magnetic Resonance Imaging (MRI) on Day 6 from onset, showed the diffuse edema and the occurrence of central herniation;the medulla was “Z-like” folded and the basal cisterns were obliterated completely. Finally she was declared dead. The imbalance between supratentorial and infratentorial pressure can lead to the occurrence of CBH. Severe edema relates to IAE and unstable structure of the posterior fossa might be the main reason for the herniation. MRI is helpful in early diagnosis. Early treatment of cerebral edema in patients with congenital abnormalities of the posterior fossa is vital for their management.

Risk Factors of Influenza-Associated Necrotizing Encephalopathy in Children

Objective: A case-control study of Influenza-Associated Necrotizing Encephalopathy (IANE) in children was conducted to explore the risk factors for the diagnosis of IANE, and to provide a predictive reference for the diagnosis of IANE. Methods: The children with IANE who received treatment in our hospital from January 2016 to December 2020 were selected as the study group, and the children with Influenza-Associated Encephalopathy (IAE) group who received treatment in the same period were selected as the control group. The blood biochemical, coagulation function and cerebrospinal fluid test results of the two groups were analyzed by univariate analysis. Receiver Operating Characteristic curve (ROC) analysis was used to determine the optimal threshold point of each index for the indicators with statistically significant differences in univariate analysis results, and multivariate Logistic stepwise regression analysis was performed according to the optimal threshold points. Results: In the IANE group, there were 32 children, including 20 males and 12 females, aged 60 (35, 84) months. There were 40 children in IAE group, including 26 males and 14 females, aged 58 (23, 97) months. Univariate results showed that serum Lactate Dehydrogenase (LDH), Cerebrospinal Fluid Lactate Dehydrogenase (CSF LDH) and Cerebrospinal Fluid Protein (CSF PRO) in the IANE group were significantly higher than those in the IAE group, and the difference between the two groups was statistically significant (P < 0.001). The optimal threshold points of blood LDH, CSF LDH and CSF PRO by ROC curve analysis were 535 U/L, 67 U/L and 0.49 g/L, respectively. Further Multivariate Logistic stepwise regression analysis showed that LDH > 535 U/L (OR = 31.264, 95% CI: 5.892 - 165.878, P < 0.001) and CSF PRO > 0.49 g/L (OR = 7.695, 95% CI: 1.052 - 56.305, P = 0.044) were independent risk factors for IANE. Conclusion: For children with influenza whose neurological symptoms appear rapidly and persist in the early stages of the disease, blood LDH > 535 U/L and CSF PRO > 0.49 g/L are independent risk factors for IANE.

Brain Complications with Influenza Infection in Children

Objectives: To summarize the characteristics and research progress of influenza-associated brain complications in children and provide references for early diagnosis and brain protection treatment. Methods: Studied published articles of influenza-associated neurocomplications in children from PubMed and summarizes them from epidemiology, clinical manifestations, diagnosis and treatment, and basic research progress. Results: Common brain complications in flu-children include febrile seizures, influenza-associated encephalopathy (IAE), acute or post-influenza encephalitis, and the most severe condition is acute necrotizing encephalopathy (ANE). However, the mechanism and relevant factors of influenza-associated brain damage have not been elucidated. Conclusion: Influenza could be accompanied by various brain lesion complications in dif ferent stages of the disease, some of which are life-threatening or leave severe neurological sequelae, such as ANE. Due to different brain injury mechanisms, specific early diagnosis and brain protection treatment for different complications are unclear or unanimous. Therefore, further classification and basic research are needed.