scholarly journals Enterovirus 71 Inhibits Pyroptosis through Cleavage of Gasdermin D

2017 ◽  
Vol 91 (18) ◽  
Author(s):  
Xiaobo Lei ◽  
Zhenzhen Zhang ◽  
Xia Xiao ◽  
Jianli Qi ◽  
Bin He ◽  
...  
Keyword(s):  
Amino Acids ◽  
Critical Role ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Severe Infection ◽  
Neurological Complications ◽  
Antiviral Response ◽  
Terminal Fragment ◽  
New Strategy ◽  
Trigger Cell Death

ABSTRACT Enterovirus 71 (EV71) can cause hand-foot-and-mouth disease (HFMD) in young children. Severe infection with EV71 can lead to neurological complications and even death. However, the molecular basis of viral pathogenesis remains poorly understood. Here, we report that EV71 induces degradation of gasdermin D (GSDMD), an essential component of pyroptosis. Remarkably, the viral protease 3C directly targets GSDMD and induces its cleavage, which is dependent on the protease activity. Further analyses show that the Q193-G194 pair within GSDMD is the cleavage site of 3C. This cleavage produces a shorter N-terminal fragment spanning amino acids 1 to 193 (GSDMD1–193). However, unlike the N-terminal fragment produced by caspase-1 cleavage, this fragment fails to trigger cell death or inhibit EV71 replication. Importantly, a T239D or F240D substitution abrogates the activity of GSDMD consisting of amino acids 1 to 275 (GSDMD1–275). This is correlated with the lack of pyroptosis or inhibition of viral replication. These results reveal a previously unrecognized strategy for EV71 to evade the antiviral response. IMPORTANCE Recently, it has been reported that GSDMD plays a critical role in regulating lipopolysaccharide and NLRP3-mediated interleukin-1β (IL-1β) secretion. In this process, the N-terminal domain of p30 released from GSDMD acts as an effector in cell pyroptosis. We show that EV71 infection downregulates GSDMD. EV71 3C cleaves GSDMD at the Q193-G194 pair, resulting in a truncated N-terminal fragment disrupted for inducing cell pyroptosis. Notably, GSDMD1–275 (p30) inhibits EV71 replication whereas GSDMD1–193 does not. These results reveal a new strategy for EV71 to evade the antiviral response.

scholarly journals Study the current scenario of hand foot mouth disease an Indian prospective

2020 ◽  
Vol 7 (7) ◽  
pp. 1558
Author(s):  
Ravi Sahota ◽  
Navpreet Kaur ◽  
Gurpal Singh ◽  
Nisha Upadhyay
Keyword(s):  
Communicable Disease ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Neurological Complications ◽  
Mouth Disease ◽  
Human Enterovirus ◽  
Cross Sectional ◽  
Timely Initiation ◽  
Human Enterovirus 71 ◽  
Hand Foot Mouth Disease

Background: The hand-foot-mouth disease (HFMD) is an acute communicable disease, mostly affecting children under 5 years of age and caused by human enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16). The usual incubation period is 3 to 7 days. Early symptoms are likely to be fever often followed by a sore throat followed by loss of appetite and general malaise. Aim and objectives was to study the trend of hand foot and mouth disease in a private hospital in Uttarakhand over 5 successive years.Methods: This cross-sectional study was carried among 297 cases of HFMD newborn screened at pediatrics department of Sahota Super-specialty hospital, Kashipur, Uttarakhand during year 2015 to 2019 after ethical clearance of institutional ethical committee. Diagnosis is coded with ICD-10. SPSS version 20 was used to calculate frequencies and percentiles.Results: Almost 29 cases of HMFD were picked in 2015, 32 cases in 2016, 43 cases in 2017, 81 cases in 2018, 112 in 2019. Fever observed in 86% cases. Neurological complications were observed in 9 (3%) cases, pneumonitis in 14 (4.7%) cases, cardiomyopathy observed in 3 (<1%) case. One death was reported.Conclusions: It is vital to screen patients with HFMD for these abnormal clinical presentations, allowing timely initiation of appropriate interventions to reduce the mortality. Increased awareness about vaccination in a developing nation like India and vaccination program at the grass root levels have eradicated certain lethal diseases.

scholarly journals Formaldehyde-Inactivated Whole-Virus Vaccine Protects a Murine Model of Enterovirus 71 Encephalomyelitis against Disease

2009 ◽  
Vol 84 (1) ◽  
pp. 661-665 ◽  
Author(s):  
Kien Chai Ong ◽  
Shamala Devi ◽  
Mary Jane Cardosa ◽  
Kum Thong Wong
Keyword(s):  
In Situ Hybridization ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Neurological Complications ◽  
Viral Culture ◽  
Adult Mice ◽  
Therapeutic Drugs ◽  
Immunohistochemistry Analysis ◽  
Old Mice

ABSTRACT Enterovirus 71 (EV71) causes childhood hand, foot, and mouth disease and neurological complications, and no vaccines or therapeutic drugs are currently available. Formaldehyde-inactivated whole-virus vaccines derived from EV71 clinical isolates and a mouse-adapted virus (MAV) were tested in a mouse model of EV71 encephalomyelitis. After only two immunizations, given to mice at 1 and 7 days of age, the MAV vaccine protected mice at 14 days of age from disease. Tissues from immunized mice were negative for virus by viral culture, reverse transcriptase PCR, immunohistochemistry analysis, and in situ hybridization. Cross-neutralizing EV71 antibodies to strains with genotypes B3, B4, and C1 to C5 generated in immunized adult mice were able to passively protect 14-day-old mice from disease.

scholarly journals Antidepressant Sertraline is a Broad-Spectrum Inhibitor of Enteroviruses Targeting Viral Entry Through Neutralization of Endolysosomal Acidification

2021 ◽  
Author(s):  
Kuan-Chi Tseng ◽  
Bang-Yan Hsu ◽  
Pin Ling ◽  
Wen-Wen Lu ◽  
Cheng-Wen Lin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Broad Spectrum ◽  
Culture Media ◽  
Antiviral Drug ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Antiviral Effect ◽  
Neurological Complications ◽  
Low Ph

Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs to treat EV71 infections. In this study, we conducted an antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug’s antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be relieved greatly by exposing virus-infected cells to extracellular low-pH culture media. Together, we have identified an FDA-approved antidepressant with the new indication for the broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.

scholarly journals Type III interferon signaling restricts enterovirus 71 infection of goblet cells

2019 ◽  
Vol 5 (3) ◽  
pp. eaau4255 ◽  
Author(s):  
Charles Good ◽  
Alexandra I. Wells ◽  
Carolyn B. Coyne
Keyword(s):  
Goblet Cell ◽  
Intestinal Epithelium ◽  
Cell Function ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Goblet Cells ◽  
Neurological Complications ◽  
Ev71 Infection ◽  
Apical Surface ◽  
Type Iii

Recent worldwide outbreaks of enterovirus 71 (EV71) have caused major epidemics of hand, foot, and mouth disease with severe neurological complications, including acute flaccid paralysis. EV71 is transmitted by the enteral route, but little is known about the mechanisms it uses to cross the human gastrointestinal tract. Using primary human intestinal epithelial monolayers, we show that EV71 infects the epithelium from the apical surface, where it preferentially infects goblet cells. We found that EV71 infection did not alter epithelial barrier function but did reduce the expression of goblet cell–derived mucins, suggesting that it alters goblet cell function. We also show that the intestinal epithelium responds to EV71 infection through the selective induction of type III interferons (IFNs), which restrict EV71 replication. Collectively, these findings define the early events associated with EV71 infections of the human intestinal epithelium and show that host IFN signaling controls replication in an IFN-specific manner.

scholarly journals Antiviral Efficacy of Flavonoids against Enterovirus 71 Infection in Vitro and in Newborn Mice

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 625 ◽  
Author(s):  
Wenwen Dai ◽  
Jinpeng Bi ◽  
Fang Li ◽  
Shuai Wang ◽  
Xinyu Huang ◽  
...  
Keyword(s):  
Protective Efficacy ◽  
Lethal Dose ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Neurological Complications ◽  
Ev71 Infection ◽  
Newborn Mice ◽  
Reported Data

Enterovirus 71 (EV71) infection is known to cause hand, foot, and mouth disease (HFMD), which is associated with neurological complications; however, there is currently no effective treatment for this infection. Flavonoids are a large group of naturally occurring compounds with multiple bioactivities, and the inhibitory effects of several flavonoids against EV71 have been studied in cell cultures; however, to date, there are no reported data on their effects in animal models. In this study, we confirmed the in vitro activities of eight flavonoids against EV71 infection, based on the inhibition of cytopathic effects. Moreover, these flavonoids were found to reduce viral genomic RNA replication and protein synthesis. We further demonstrated the protective efficacy of these flavonoids in newborn mice challenged with a lethal dose of EV71. Apigenin, luteolin, kaempferol, formononetin, and penduletin conferred survival protection of 88.89%, 91.67%, 88.89%, 75%, and 66.67%, respectively, from the lethal EV71 challenge. In addition, isorhamnetin provided the highest mice survival protection of 100% at a dose of 10 mg/kg. This study, to the best of our knowledge, is the first to evaluate the in vivo anti-EV7l activities of multiple flavonoids, and we accordingly identified flavonoids as potential leading compounds for anti-EV71 drug development.

scholarly journals Interleukin-27 as a Novel Biomarker for Early Cardiopulmonary Failure in Enterovirus 71-Infected Children with Central Nervous System Involvement

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Mingyuan Huang ◽  
Wenjing Du ◽  
Jun Liu ◽  
Haiyang Zhang ◽  
Longbin Cao ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clinical Stage ◽  
Central Nervous System Involvement ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Neurological Complications ◽  
High Morbidity ◽  
Cns Involvement ◽  
Cardiopulmonary Failure

Enterovirus 71 (EV71) is a major pathogen for severe hand, foot, and mouth disease (HFMD), which leads to severe neurological complications and has high morbidity and mortality. Reliable biomarker for the prediction of deterioration in EV71-infected children with central nervous system (CNS) involvement may reduce the cardiopulmonary failure and mortality. Here, we found that serum IL-27 levels were significantly higher in stage III EV71-infected HFMD patients with early cardiopulmonary failure and strong correlation with CRP levels.IL27p28polymorphisms (rs153109, rs17855750, and rs181206) did not influence IL-27 production, and these three SNPs were not associated with EV71 infection risk and clinical stage. IL-27 can be used as an prediction indicator for early cardiopulmonary failure in EV71-infected children with CNS involvement.

scholarly journals Isolating Asian enterovirus 71 subgenogroup C4 in two Austrian clinical samples from 2004

2008 ◽  
Vol 13 (28) ◽  
Author(s):  
H. P. Huemer ◽  
B Ortner ◽  
C-W Huang ◽  
D Schmid ◽  
I Mutz ◽  
...  
Keyword(s):  
Public Health ◽  
Pulmonary Oedema ◽  
Mainland China ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Neurological Complications ◽  
Mouth Disease ◽  
Clinical Samples ◽  
Foot And Mouth ◽  
Enterovirus Type

Hamaguchi et al. recently reported on the on the occurrence of enterovirus type 71 (EV71) subgenogroup C4 in Japan [1]. According to the authors, this strain may have emerged in mainland China and in Taiwan. EV71 subgenogroup C4 has recently gained public health interest following reports of an ongoing outbreak in China and Vietnam in 2008: In June 2008, more than 176,000 cases of hand, foot and mouth disease (HFMD) were reported in China alone, and at least 24 deaths have been attributed to EV71 [2,3]. In the largest and most severe EV71-associated HFMD outbreak in Taiwan in 1998, 405 children had severe neurological complications and/or pulmonary oedema; 78 children died [4].

scholarly journals Antidepressant Sertraline Is a Broad-Spectrum Inhibitor of Enteroviruses Targeting Viral Entry through Neutralization of Endolysosomal Acidification

Viruses ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 109
Author(s):  
Kuan-Chi Tseng ◽  
Bang-Yan Hsu ◽  
Pin Ling ◽  
Wen-Wen Lu ◽  
Cheng-Wen Lin ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Viral Entry ◽  
Broad Spectrum ◽  
Culture Media ◽  
Antiviral Drug ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Antiviral Effect ◽  
Neurological Complications ◽  
Low Ph

Enterovirus 71 (EV71) is an etiological agent of hand foot and mouth disease and can also cause neurological complications in young children. However, there are no approved drugs as of yet to treat EV71 infections. In this study, we conducted antiviral drug screening by using a Food and Drug Administration (FDA)-approved drug library. We identified five drugs that showed dose-dependent inhibition of viral replication. Sertraline was further characterized because it exhibited the most potent antiviral activity with the highest selectivity index among the five hits. The antiviral activity of sertraline was noted for other EV serotypes. The drug’s antiviral effect is not likely associated with its approved indications as an antidepressant and its mode-of-action as a selective serotonin reuptake inhibitor. The time-of-addition assay revealed that sertraline inhibited an EV71 infection at the entry stage. We also showed that sertraline partitioned into acidic compartments, such as endolysosomes, to neutralize the low pH levels. In agreement with the findings, the antiviral effect of sertraline could be greatly relieved by exposing virus-infected cells to extracellular low-pH culture media. Ultimately, we have identified a use for an FDA-approved antidepressant in broad-spectrum EV inhibition by blocking viral entry through the alkalization of the endolysosomal route.

scholarly journals DNA aptamer against EV-A71 VP1 protein: selection and application

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xinran Zou ◽  
Jing Wu ◽  
Jiaqi Gu ◽  
Li Shen ◽  
Lingxiang Mao
Keyword(s):  
Protein Expression ◽  
Enterovirus 71 ◽  
Virus Detection ◽  
Foot And Mouth Disease ◽  
High Specificity ◽  
Antiviral Effect ◽  
Neurological Complications ◽  
Dna Aptamer ◽  
Manufacturing Cost

Abstract Background Enterovirus 71 (EV-A71) is a highly infectious pathogen associated with hand, foot and mouth disease, herpangina, and various neurological complications, so it is important for the early detection and treatment of EV-A71. An aptamer is a nucleotide sequence that screened in vitro by the technology named systematic evolution of ligands by exponential enrichment technology (SELEX). Similar to antibodies, aptamers can bind to the targets with high specificity and affinity. Besides, emerging aptamers have many advantages comparing with antibodies, such as ease of synthesis and modification, having a wide variety of target materials, low manufacturing cost and easy flexibility in amending. Therefore, aptamers are promising in virus detection and anti-virus therapy. Methods Aptamers were selected by SELEX. Specificity, affinity and second structure were used to characterize the selected aptamers. Chemiluminescence was adopted to build an aptamer-based detection method for EV-A71. Cytopathogenic effects trial, the level of intracellular EV-A71 RNA and protein expression were used to evaluate the antiviral effect of the selected aptamers. Results Three DNA aptamers with high specificity and affinity for EV-A71structual protein VP1 were screened out. A rapid chemiluminutesescence aptamer biosensor for EV-A71 detection was designed out. The selected aptamers could inhibit the RNA replication and protein expression of EV-A71 in RD cells and ameliorate the cytopathogenic effects. Conclusions The aptamers against EV-A71 have the potentiality to be applied as attractive candidates used for EV-A71 detection and treatment in the future.

scholarly journals Enterovirus 71 structural viral protein 1 promotes mouse Schwann cell autophagy via endoplasmic reticulum stress-mediated peripheral myelin protein 22 upregulation

2018 ◽  
Author(s):  
Pei-qing Li ◽  
Si-da Yang ◽  
Dan-dan Hu ◽  
Dan WeEI ◽  
Jing Lu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Viral Protein ◽  
Neuronal Damage ◽  
Enterovirus 71 ◽  
Foot And Mouth Disease ◽  
Neurological Complications ◽  
Immunofluorescent Staining ◽  
Peripheral Myelin Protein 22 ◽  
Viral Protein 1

AbstractEnterovirus 71 (EV71) accounts for the majority of hand, foot and mouth disease-related deaths due to fatal neurological complications. The clinical observations and animal models found the early invasion of nervous system, and the demyelinating phenomenon was observed. As one of the receptors of EV71 structural viral protein 1 (VP1), SCARB2 mainly exists on the myelin sheath. EV71 VP1 can promote viral replication through inducing autophagy in neuron cells. This study aims to investigate the role and mechanism of VP1 in autophagy of mouse Schwann cells (MSCs). An EV71 VP1-expressing vector (pEGFP-C3-VP1) was generated and transfected into MSCs. Transmission electron microscopy (TEM) and Western blot analysis of the autophagy marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) were used to assess autophagy in the cells. Real-time PCR and immunofluorescent staining were performed to determine the expression of PMP22. Small interfering RNA against PMP22 was employed to investigate the role of PMP22 in MSCs autophagy. Selective endoplasmic reticulum (ER) stress inhibitor salubrinal (SAL) was employed to determine whether PMP22 is mediated by ER stress. Our results demonstrated that VP1 played a promotive role in MSC autophagy. Overexpression of VP1 upregulated PMP22. PMP22 deficiency downregulated LC3B and thus inhibited autophagy. Furthermore, PMP22 expression was significantly suppressed by SAL. VP1 promotes MSC autophagy through upregulating ER stress-mediated PMP22 expression. VP1/ER stress/ PMP22 axis in autophagy may be a potential therapeutic target for EV71 infection-induced fatal neuronal damage.

Sign in / Sign up

Export Citation Format

Share Document