BACKGROUND Acute flaccid paralysis(AFP)and neurogenic respiratory failure rarely occur in children.At the end of 2018,some children with such symptoms were admitted to our hospital.In this study,we aimed to assess two...BACKGROUND Acute flaccid paralysis(AFP)and neurogenic respiratory failure rarely occur in children.At the end of 2018,some children with such symptoms were admitted to our hospital.In this study,we aimed to assess two children with AFP and neurogenic respiratory failure associated with enterovirus D68(EV-D68).CASE SUMMARY Two children admitted to our hospital presented with symptoms and imaging results different from those of acute disseminated encephalomyelitis and hand,foot,and mouth disease.Their main symptoms were AFP and neurogenic respiratory failure.Magnetic resonance imaging showed severe inflammatory injury mainly to the anterior horn cells of the spinal cord.Blood and cerebrospinal fluid samples were collected to assess for pathogens,including bacteria,tuberculosis,cryptococcus,herpes virus,and coxsackie virus,and the results were negative.At the beginning,the two cases were not assessed for EV-D68 in the nasopharyngeal,blood,and cerebrospinal fluid specimens.About 2 mo later,EVD68 was detected in the stool sample of one of the cases.The symptom of AFP was caused by injury to the anterior horn cells at levels C5-L5 of the spinal cord,while neurogenic respiratory failure was at levels C3-C5.CONCLUSION We should pay attention to the detection and diagnosis of EV-D68 and make efforts to develop antivirus drugs and vaccines.展开更多
Enterovirus D68 (EV-D68) infection causes severe acute respiratory infection and severe neurological complications, such as acute flaccid myelitis (AFM), in children. However, although EV-D68 has pandemic potential, n...Enterovirus D68 (EV-D68) infection causes severe acute respiratory infection and severe neurological complications, such as acute flaccid myelitis (AFM), in children. However, although EV-D68 has pandemic potential, no effective drugs or vaccines are currently clinically available. Furthermore, EV-D68 infection-induced inflammatory response and cell death are not fully understood. In this study, we demonstrated that several inflammatory cytokines were upregulated in a multiplicity of infection (MOI) dependent manner in EV-D68-infected human rhabdomyosarcoma (RD) cells. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) confirmed that tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), C-C motif chemokine ligand-5 (CCL-5), and CXC motif chemokine ligand-5 (CXCL-5) mRNA levels were highly upregulated after EV-D68 infection. IL-1β processing and maturation mediated by caspase-8 was inhibited by the caspase-8 inhibitor Z-IETD-FMK. EV-D68 infection activates caspase-8 to mediate IL-1β maturation and secretion. Additionally, EV-D68 activated cell death-related proteins such as caspase-3, poly (ADP-ribose) polymerase 1 (PARP-1), phosphorylation of Mixed Lineage Kinase domain-like protein (pMLKL), and gasdermin E (GSDME). Thus, EV-D68 infection activates caspase-8, which triggers the necroptosis and apoptosis pathways. Overall, our data suggest that caspase-8 activation is associated with the inflammatory response and cell death in EV-D68-infected RD cells. This mechanism represents a novel target for the treatment of EV-D68 infection by inhibiting caspase-8 activation.展开更多
Enterovirus D68(EV-D68)can cause respiratory diseases and acute flaccid paralysis,posing a great threat to public health.Interferons are cytokines secreted by host cells that have broad-spectrum antiviral effects,indu...Enterovirus D68(EV-D68)can cause respiratory diseases and acute flaccid paralysis,posing a great threat to public health.Interferons are cytokines secreted by host cells that have broad-spectrum antiviral effects,inducing the expression of hundreds of interferon-stimulated genes(ISGs).EV-D68 activates ISG expression early in infection,but at a later stage,the virus suppresses ISG expression,a strategy evolved by EV-D68 to antagonize interferons.Here,we explore a host protein,suppressor of cytokine signaling 3(SOCS3),is upregulated during EV-D68 infection and antagonizes the antiviral effects of type I interferon.We subsequently demonstrate that the structural protein of EV-D68 upregulated the expression of RFX7,a transcriptional regulator of SOCS3,leading to the upregulation of SOCS3 expression.Further exploration revealed that SOCS3 plays its role by inhibiting the phosphorylation of signal transducer and activator of transcription 3(STAT3).The expression of SOCS3 inhibited the expression of ISG,thereby inhibiting the antiviral effect of type I interferon and promoting EV-D68 transcription,protein production,and viral titer.Notably,a truncated SOCS3,generated by deleting the kinase inhibitory region(KIR)domain,failed to promote replication and translation of EV-D68.Based on the above studies,we designed a short peptide named SOCS3 inhibitor,which can specifically bind and inhibit the KIR structural domain of SOCS3,significantly reducing the RNA and protein levels of EV-D68.In summary,our results demonstrated a novel mechanism by which EV-D68 inhibits ISG transcription and antagonizes the antiviral responses of host type I interferon.展开更多
Human enterovirus(EV)infections can lead to various manifestations,with variable correlations between genotypes and symptoms.Human enterovirus D68(EV-D68)was considered to be associated with acute respiratory disease ...Human enterovirus(EV)infections can lead to various manifestations,with variable correlations between genotypes and symptoms.Human enterovirus D68(EV-D68)was considered to be associated with acute respiratory disease and acute flaccid myelitis.In this short report,both EV-D68 and poliovirus 3 were detected in the stool of a hospitalized 5-month child who presented with acute respiratory symptoms and who was recently vaccinated with oral polio vaccine(OPV),using a metatranscriptomic high-throughput sequencing method.The nearly full-length genome sequences with complete open reading frames of EV-D68 and poliovirus 3 were assembled.One previously-reported neurovirulence-related amino acid substitution(T860N)in the EV-D68 VP1 region was observed,but the patient showed no neurological symptoms.More attention should be paid to EV-D68,and continuous multiple syndrome-based surveillance on non-polio enterovirus is called for.展开更多
Background:Rhino-enteroviruses,particularly enterovirus strain D68(EV-D68),have been associated with severe respiratory distress in children.The goal of this study was to compare the long-term outcomes of children wit...Background:Rhino-enteroviruses,particularly enterovirus strain D68(EV-D68),have been associated with severe respiratory distress in children.The goal of this study was to compare the long-term outcomes of children with EV-D68 infection to that of children with other enterovirus/rhinovirus.Methods:Nasopharyngeal swabs from 174 children presenting with respiratory distress were tested by PCR for respiratory viruses.The primary outcome was diagnosis of a chronic respiratory condition within the followup period.Admission to intensive care,and length of stay were recorded.Odds ratios were determined using multinomial logistic regression.Results:During 5 years of follow-up,the crude odds of diagnosis with a chronic respiratory condition were significantly more likely in EV-D68 cases(OR:1.95,95%CI:1.02,3.82),but failed to remain significant after adjusting for a past history of asthma.Upon admission for a primary concern of asthma,length of stay both in hospital and intensive care were significantly longer in EV-D68 cases(OR:2.10[95%CI:1.56,2.82,p<0.001])and(OR:5.18[95%CI:1.90,6.28,p<0.001]),respectively.After adjustment for a history of asthma,EV-D68 cases had significantly longer length of stay in hospital,admitted for 1.94 days for each day that controls were admitted(95%CI:1.40,2.68).In admissions to intensive care,EV-D68 cases spent 2.74 days for each day of admission in controls(95%CI:1.62,4.97,p<0.001).Conclusions:Ours is first study to assess prognostic respiratory outcomes of patients infected with EV-D68 in childhood.Our study finds that EV-D68 cases were significantly more likely be hospitalized for longer than other enterovirus/rhinovirus controls in subsequent admissions for respiratory distress.Need for intensive care was significantly longer in EV-D68 infections.Our next steps will be validation in a larger sample size.展开更多
文摘BACKGROUND Acute flaccid paralysis(AFP)and neurogenic respiratory failure rarely occur in children.At the end of 2018,some children with such symptoms were admitted to our hospital.In this study,we aimed to assess two children with AFP and neurogenic respiratory failure associated with enterovirus D68(EV-D68).CASE SUMMARY Two children admitted to our hospital presented with symptoms and imaging results different from those of acute disseminated encephalomyelitis and hand,foot,and mouth disease.Their main symptoms were AFP and neurogenic respiratory failure.Magnetic resonance imaging showed severe inflammatory injury mainly to the anterior horn cells of the spinal cord.Blood and cerebrospinal fluid samples were collected to assess for pathogens,including bacteria,tuberculosis,cryptococcus,herpes virus,and coxsackie virus,and the results were negative.At the beginning,the two cases were not assessed for EV-D68 in the nasopharyngeal,blood,and cerebrospinal fluid specimens.About 2 mo later,EVD68 was detected in the stool sample of one of the cases.The symptom of AFP was caused by injury to the anterior horn cells at levels C5-L5 of the spinal cord,while neurogenic respiratory failure was at levels C3-C5.CONCLUSION We should pay attention to the detection and diagnosis of EV-D68 and make efforts to develop antivirus drugs and vaccines.
基金the China National Institute of Food and Drug Control for providing the Fermon strain(GenBank accession number AY426531)and pBluescriptII SK-vector-EV-D6815296the Shanghai Science and Technology Commission Medical Project(grant 21Y11901300)+1 种基金the Contagious and Infectious Diseases Specialist Alliance(SHDC22021317)the National Key Research and Development Program of China(2022YFC2704900).
文摘Enterovirus D68 (EV-D68) infection causes severe acute respiratory infection and severe neurological complications, such as acute flaccid myelitis (AFM), in children. However, although EV-D68 has pandemic potential, no effective drugs or vaccines are currently clinically available. Furthermore, EV-D68 infection-induced inflammatory response and cell death are not fully understood. In this study, we demonstrated that several inflammatory cytokines were upregulated in a multiplicity of infection (MOI) dependent manner in EV-D68-infected human rhabdomyosarcoma (RD) cells. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) confirmed that tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), C-C motif chemokine ligand-5 (CCL-5), and CXC motif chemokine ligand-5 (CXCL-5) mRNA levels were highly upregulated after EV-D68 infection. IL-1β processing and maturation mediated by caspase-8 was inhibited by the caspase-8 inhibitor Z-IETD-FMK. EV-D68 infection activates caspase-8 to mediate IL-1β maturation and secretion. Additionally, EV-D68 activated cell death-related proteins such as caspase-3, poly (ADP-ribose) polymerase 1 (PARP-1), phosphorylation of Mixed Lineage Kinase domain-like protein (pMLKL), and gasdermin E (GSDME). Thus, EV-D68 infection activates caspase-8, which triggers the necroptosis and apoptosis pathways. Overall, our data suggest that caspase-8 activation is associated with the inflammatory response and cell death in EV-D68-infected RD cells. This mechanism represents a novel target for the treatment of EV-D68 infection by inhibiting caspase-8 activation.
基金This work was supported by the National Natural Science Foundation of China(32170144).
文摘Enterovirus D68(EV-D68)can cause respiratory diseases and acute flaccid paralysis,posing a great threat to public health.Interferons are cytokines secreted by host cells that have broad-spectrum antiviral effects,inducing the expression of hundreds of interferon-stimulated genes(ISGs).EV-D68 activates ISG expression early in infection,but at a later stage,the virus suppresses ISG expression,a strategy evolved by EV-D68 to antagonize interferons.Here,we explore a host protein,suppressor of cytokine signaling 3(SOCS3),is upregulated during EV-D68 infection and antagonizes the antiviral effects of type I interferon.We subsequently demonstrate that the structural protein of EV-D68 upregulated the expression of RFX7,a transcriptional regulator of SOCS3,leading to the upregulation of SOCS3 expression.Further exploration revealed that SOCS3 plays its role by inhibiting the phosphorylation of signal transducer and activator of transcription 3(STAT3).The expression of SOCS3 inhibited the expression of ISG,thereby inhibiting the antiviral effect of type I interferon and promoting EV-D68 transcription,protein production,and viral titer.Notably,a truncated SOCS3,generated by deleting the kinase inhibitory region(KIR)domain,failed to promote replication and translation of EV-D68.Based on the above studies,we designed a short peptide named SOCS3 inhibitor,which can specifically bind and inhibit the KIR structural domain of SOCS3,significantly reducing the RNA and protein levels of EV-D68.In summary,our results demonstrated a novel mechanism by which EV-D68 inhibits ISG transcription and antagonizes the antiviral responses of host type I interferon.
基金supported by the Key Project of Medicine Discipline of Guangzhou(2021-2023-11)the Science and Technology Project of Guangzhou(2023A03J0447).
文摘Human enterovirus(EV)infections can lead to various manifestations,with variable correlations between genotypes and symptoms.Human enterovirus D68(EV-D68)was considered to be associated with acute respiratory disease and acute flaccid myelitis.In this short report,both EV-D68 and poliovirus 3 were detected in the stool of a hospitalized 5-month child who presented with acute respiratory symptoms and who was recently vaccinated with oral polio vaccine(OPV),using a metatranscriptomic high-throughput sequencing method.The nearly full-length genome sequences with complete open reading frames of EV-D68 and poliovirus 3 were assembled.One previously-reported neurovirulence-related amino acid substitution(T860N)in the EV-D68 VP1 region was observed,but the patient showed no neurological symptoms.More attention should be paid to EV-D68,and continuous multiple syndrome-based surveillance on non-polio enterovirus is called for.
基金supported by the Research Institute of St.Joe’s Healthcare Hamilton.
文摘Background:Rhino-enteroviruses,particularly enterovirus strain D68(EV-D68),have been associated with severe respiratory distress in children.The goal of this study was to compare the long-term outcomes of children with EV-D68 infection to that of children with other enterovirus/rhinovirus.Methods:Nasopharyngeal swabs from 174 children presenting with respiratory distress were tested by PCR for respiratory viruses.The primary outcome was diagnosis of a chronic respiratory condition within the followup period.Admission to intensive care,and length of stay were recorded.Odds ratios were determined using multinomial logistic regression.Results:During 5 years of follow-up,the crude odds of diagnosis with a chronic respiratory condition were significantly more likely in EV-D68 cases(OR:1.95,95%CI:1.02,3.82),but failed to remain significant after adjusting for a past history of asthma.Upon admission for a primary concern of asthma,length of stay both in hospital and intensive care were significantly longer in EV-D68 cases(OR:2.10[95%CI:1.56,2.82,p<0.001])and(OR:5.18[95%CI:1.90,6.28,p<0.001]),respectively.After adjustment for a history of asthma,EV-D68 cases had significantly longer length of stay in hospital,admitted for 1.94 days for each day that controls were admitted(95%CI:1.40,2.68).In admissions to intensive care,EV-D68 cases spent 2.74 days for each day of admission in controls(95%CI:1.62,4.97,p<0.001).Conclusions:Ours is first study to assess prognostic respiratory outcomes of patients infected with EV-D68 in childhood.Our study finds that EV-D68 cases were significantly more likely be hospitalized for longer than other enterovirus/rhinovirus controls in subsequent admissions for respiratory distress.Need for intensive care was significantly longer in EV-D68 infections.Our next steps will be validation in a larger sample size.
