Molecular Characterization of an Enterovirus 71 Causing Neurological Disease in Germany

Kehle, Johannes; Roth, Bernhard; Metzger, Christoph; Pfitzner, Artur J. P.; Enders, Gisela

doi:10.1080/13550280390173364

Cited by 40 publications

(24 citation statements)

References 8 publications

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“…3C sequence analysis of 395 EV71 strains isolated in Taiwan between 1998 and 2003 identified one patient with a 3C K52R mutation who presented with severe CNS involvement (supplemental Table 1). 3 These results support a correlation between our EV71 mouse model and a clinical case. In addition, several isolated strains with mutations flanking the 3C Lys-52 residue were also identified, including mutations K45R, I47V, and V49I associated with the clinical diagnosis of more mild illness rather than CNS involvement (supplemental Table 1).…”

Section: Ubc9 Binding Capacity Determines the Extent Of Ev71 3csupporting

confidence: 77%

“…6D. Although the incidence rates of the 3C sumoylation-defective mutants were not high in clinically associated EV71 strains, 3 these results provide a potential correlation between EV71 3C sumoylation and disease severity.…”

Section: Ubc9 Binding Capacity Determines the Extent Of Ev71 3cmentioning

confidence: 79%

“…However, during the 1998 epidemic in Taiwan, EV71 infection was associated with severe central nervous system (CNS) diseases and complications, including encephalitis, aseptic meningitis, brain stem encephalitis, and rapidly fatal pulmonary edema and hemorrhage (2)(3)(4)(5). Very little is known about the molecular basis of EV71-elicited neuropathogenesis.…”

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confidence: 99%

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Sumoylation-promoted Enterovirus 71 3C Degradation Correlates with a Reduction in Viral Replication and Cell Apoptosis

Chen

Chang

Wang

et al. 2011

Journal of Biological Chemistry

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Enterovirus 71 (EV71), a member of the Picornaviridae family, may cause serious clinical manifestations associated with the central nervous system. Enterovirus 3C protease is required for virus replication and can trigger host cell apoptosis via cleaving viral polyprotein precursor and cellular proteins, respectively. Although the role of the 3C protease in processing viral and cellular proteins has been established, very little is known about the modulation of EV71 3C function by host cellular factors. Here, we show that sumoylation promotes EV71 3C protein ubiquitination for degradation, correlating with a decrease of EV71 in virus replication and cell apoptosis. SUMO E2-conjugating enzyme Ubc9 was identified as an EV71 3C-interacting protein. Further studies revealed that EV71 3C can be SUMO (small ubiquitin-like modifier)-modified at residue Lys-52. Sumoylation down-regulated 3C protease activity in vitro and also 3C protein stability in cells, in agreement with data suggesting 3C K52R protein induced greater substrate cleavage and apoptosis in cells. More importantly, the recombinant EV71 3C K52R virus infection conferred more apoptotic phenotype and increased virus levels in culture cells, which also correlated with a mouse model showing increased levels of viral VP1 protein in intestine and neuron loss in the spinal cord with EV71 3C K52R recombinant viral infection. Finally, we show that EV71 3C amino acid residues 45-52 involved in Ubc9 interaction determined the extent of 3C sumoylation and protein stability. Our results uncover a previously undescribed cellular regulatory event against EV71 virus replication and host cell apoptosis by sumoylation at 3C protease.Enterovirus 71 (EV71), 2 similar to poliovirus, belongs to the genus Enterovirus of the Picornaviridae family. EV71 infection usually causes mild symptoms in childhood, such as herpangina or exanthema also known as hand, foot, and mouth disease (1). However, during the 1998 epidemic in Taiwan, EV71 infection was associated with severe central nervous system (CNS) diseases and complications, including encephalitis, aseptic meningitis, brain stem encephalitis, and rapidly fatal pulmonary edema and hemorrhage (2-5). Very little is known about the molecular basis of EV71-elicited neuropathogenesis.EV71 possesses a single-stranded RNA genome of ϳ7500 nucleotides in length with positive polarity (6). Although the replication mechanism of EV71 is largely unknown, studies of other members in the Picornaviridae family revealed that virus RNA encodes a large polyprotein (ϳ200 kDa), which is processed by viral protease 2A and 3C into 27 cleavage intermediates and end products (7). Most of the proteolytic reactions are accomplished by viral 3C protease, whereas viral 2A protease catalyzes only two cleavages on the polyprotein. In addition to viral precursor protein processing, enterovirus 3C protease is also involved in the inhibition of essential host functions such as transcription, cytoskeletal integrity, and polyadenylation (8 -11). For instance, polio...

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Section: Ubc9 Binding Capacity Determines the Extent Of Ev71 3csupporting

confidence: 77%

Section: Ubc9 Binding Capacity Determines the Extent Of Ev71 3cmentioning

confidence: 79%

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Sumoylation-promoted Enterovirus 71 3C Degradation Correlates with a Reduction in Viral Replication and Cell Apoptosis

Chen

Chang

Wang

et al. 2011

Journal of Biological Chemistry

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“…However, the reported number of cases of neurological complications was small compared to those in other reports (14,17,22,29). There are several explanations to account for this finding.…”

Section: Discussioncontrasting

confidence: 51%

Clinical and Etiological Characteristics of Enterovirus 71-Related Diseases during a Recent 2-Year Period in Korea

et al. 2010

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Human enterovirus 71 (EV 71) has caused large-scale outbreaks of hand-foot-and-mouth disease (HFMD), particularly in the Asian-Pacific region. In this study, we report a major outbreak of EV 71 infection in Korea and describe the clinical differences between EV 71 and non-EV 71 enterovirus infections. We prospectively enrolled patients with suspected viral infections during a recent 2-year period through a nationwide surveillance system. We identified 719 patients with suspected HFMD or herpangina using real-time PCR and genotyping based on VP1 sequence analysis. The major pathogen causing HFMD changed substantially from 2008 to 2009, with EV 71 becoming the most common cause of HFMD in Korea in 2009. We successfully identified the enteroviral genotypes for 218 of the 719 patients. Patients with EV 71 infections tended to be younger than those with non-EV 71 enteroviral infections and presented with HFMD and meningoencephalitis. In addition, the occurrence of fever, headache, and neck stiffness was significantly higher in patients with EV 71 infections. Multivariable analysis showed that for patients presenting with HFMD, fever, or a sore throat, each covariate was independently associated with EV 71 infection; the adjusted odds ratios (with 95% confidence intervals in parentheses) for these variables were 31.86 (10.04 to 101.09), 4.76 (1.71 to 13.25), and 0.18 (0.04 to 0.77), respectively. Our results indicate that EV 71 was a major cause of HFMD in Korea during the study period. In addition, we found that clinical symptoms may be helpful in the early identification of patients with EV 71 infections.Human enterovirus 71 (EV 71) is an important emerging pathogen of hand-foot-and-mouth disease (HFMD) (1, 6, 30). In particular, several major outbreaks of EV 71 have been documented in the Asia-Pacific region since 1997 (3,4,7,9,25). EV 71 infection causes HFMD, a common exanthema of young children that is characterized by a fever, rashes on the palms and the bottoms of the feet, and ulcers in the oral cavity. In general, patients with HFMD experience a mild course of disease; however, some patients develop severe neurological complications, especially as a result of EV 71 (18).Given that EV 71 infection could cause severe neurological complications, its early detection in patients with HFMD is an important part of intensive care efforts and efforts to prevent mortality. Unfortunately, current methods for the detection of EV 71 do not enable early detection (23). Here we report an outbreak of EV 71 infection in Korea. As part of this nationwide surveillance study, we examined the clinical differences between EV 71 and non-EV 71 enteroviral infections, and we investigated whether these differences are clinically applicable to the early detection of EV 71 in patients with complications of HFMD. MATERIALS AND METHODS Patients.A nationwide surveillance system for infection with enterovirus (EV) in Korea was initiated in 2005. Sixty-two clinics (8 primary clinics, 14 secondary hospitals, and 40 tertiary hospitals located...

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“…Many other countries including Japan, Singapore, Vietnam, and Peninsular Malaysia have experienced cyclical epidemics that occur every 2-3 years [6,7]. Lately, this virus has been reported to cause several HFMD outbreaks with cases not only presented with the typical HFMD syndromes but also with neurological diseases such as aseptic meningitis, encephalitis, and meningoencephalitis [8][9][10][11][12]. EV-A71 was also known to cause common non-polio EV (NPEV) associated with poliomyelitis-like paralysis in HFMD cases [13,14].…”

Section: Introductionmentioning

confidence: 99%

Human enterovirus A71 (EV-A71) isolated from acute flaccid paralysis patients without symptoms of hand foot and mouth disease

2018

J App Biol Biotech

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Background: Human enterovirus A-71 (EV-A71) is one of the causative agents for hand, foot, and mouth disease (HFMD). It is also reported to cause acute flaccid paralysis (AFP) during HFMD outbreaks and very rare to isolate them from non-HFMD cases. Materials and Methods: A total of 2809 stool samples from AFP cases were cultured on RD and L20B cells. Positive on L20B was screened for poliovirus and those only positive on RD were subjected to non-polio EV (NPEV) screening by real-time polymerase chain reaction. Phylogenetic analysis using VP1 and VP4 gene was constructed. Results: A total of 74 EVs were isolated, 61 were NPEV and 13 were poliovirus Sabin like. The NPEVs were identified as coxsackieviruses, echoviruses, and EV-A71. Phylogenetic analysis showed that this EV-A71 belong to subgenogroup B5. Conclusions: The discovery of EV-A71 which caused AFP in patients but not related or associated with HFMD outbreaks showed that this virus could circulate independently. It should be investigated thoroughly as their ability to cause paralysis on the eradication of polio.

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Molecular Characterization of an Enterovirus 71 Causing Neurological Disease in Germany

Cited by 40 publications

References 8 publications

Sumoylation-promoted Enterovirus 71 3C Degradation Correlates with a Reduction in Viral Replication and Cell Apoptosis

Sumoylation-promoted Enterovirus 71 3C Degradation Correlates with a Reduction in Viral Replication and Cell Apoptosis

Clinical and Etiological Characteristics of Enterovirus 71-Related Diseases during a Recent 2-Year Period in Korea

Human enterovirus A71 (EV-A71) isolated from acute flaccid paralysis patients without symptoms of hand foot and mouth disease

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