Association of EV71 3C polymorphisms with clinical severity

Ma, Hsuan-Yin; Lu, Chi-Jen; Tsao, Kuo‐Chien; Shih, Hsiu‐Ming; Cheng, Ai-Ling; Huang, Li‐Min; Chang, Luan‐Yin

doi:10.1016/j.jmii.2016.12.006

Cited by 12 publications

(9 citation statements)

References 17 publications

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“…In addition, the mutations in P3 region have been reported to impact on neurovirulence. For example, the polymorphism of EV71 3C at the 79th AA was shown to be associated with clinical severity . The T79V mutant caused the most severe clinical presentations as compared with other T79I and T79A mutants.…”

Section: Discussionmentioning

confidence: 99%

Sequence analysis‐based characterization and identification of neurovirulence‐associated variants of 36 EV71 strains from China

Wang

Zhao

et al. 2018

Journal of Medical Virology

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Enterovirus 71 (EV71) is the main pathogen of hand-foot-mouth disease (HFMD) and causes several neurological complications. As new strains of EV71 are constantly discovered, it is important to understand the genomic characteristics of the viruses and the mechanism of virulence. Herein, we isolated five strains of EV71 from HFMD patients with or without neurovirulence and sequenced their whole genomes. We then performed whole genome sequence analysis of totally 36 EV71 strains. The phylogenetic analysis of the VP1 region revealed all five isolated strains are clustered into C4a of C4 subgenotype. In addition, by comparing the complete genome sequences of 36 strains, 253 variable amino acid positions were found, 14 of which were identified to be associated with neurovirulence (P < 0.05). Moreover, a similar pattern of amino acid variants combination was identified in four strains without neurovirulence, indicating this type of variant pattern might be associated with avirulence. The strains with neurovirulence appeared to be distinguished from those without neurovirulence by the variants in VP1 and P2 regions, implying VP1 and P2 are the important regions associated with neurovirulence. Indeed, 3-D modeling of VP1 and P2 regions of non-neurovirulent and neurovirulent strains revealed that the different variants resulted in different protein structures and amino acid composition of ligand binding site, which might account for their difference in neurovirulence. In summary, our study reveals 14 variable amino acid positions of VP1, P2 and P3 regions are related to the virulence and that mutations in the capsid proteins of EV71 might contribute to neurovirulence.

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Section: Discussionmentioning

confidence: 99%

Sequence analysis‐based characterization and identification of neurovirulence‐associated variants of 36 EV71 strains from China

Wang

Zhao

et al. 2018

Journal of Medical Virology

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“…To our knowledge, nonstructural proteins 2A and 3C are the key proteases in the EV71 proliferation process and are closely related with clinical severity. 14,[52][53][54] Because nonstructural proteins have been regarded as drug targets, 55,56 we cloned the 2A and 3C genes separately into the pFlag-CMV-2 vector to investigate whether LJ04 exerts an effect on protease activity. In this assay, eIF4G, which is a substrate of both 2A and 3C, was employed as the indicator, 57,58 and β-actin was used as the control.…”

Section: Discussionmentioning

confidence: 99%

“…The results from the time‐of‐addition and penetration assays both suggest that LJ04 also exerts an inhibitory effect after EV71 entry into cells, and thus, we investigated the targets of LJ04. To our knowledge, nonstructural proteins 2A and 3C are the key proteases in the EV71 proliferation process and are closely related with clinical severity . Because nonstructural proteins have been regarded as drug targets, we cloned the 2A and 3C genes separately into the pFlag‐CMV‐2 vector to investigate whether LJ04 exerts an effect on protease activity.…”

Section: Discussionmentioning

confidence: 99%

Virucidal activity and the antiviral mechanism of acidic polysaccharides against Enterovirus 71 infectionin vitro

Cui

Liu

et al. 2020

Microbiology and Immunology

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Enterovirus 71 (EV71) is the predominant pathogen for severe hand, foot, and mouth disease (HFMD) in children younger than 5 years, and currently no effective drugs are available for EV71. Thus, there is an urgent need to develop new drugs for the control of EV71 infection. In this study, LJ04 was extracted from Laminaria japonica using diethylaminoethyl cellulose‐52 with 0.4 mol/l NaCl as the eluent, and its virucidal activity was evaluated based on its cytopathic effects on a microplate. LJ04 is composed of fucose, galactose, and mannose and mainly showed good virucidal activity against EV71. The antiviral mechanisms of LJ04 were the direct inactivation of the virus, the blockage of virus binding, disruptions to viral entry, and weak inhibitory activity against the nonstructural protein 3C. The two most important findings from this study were that LJ04 inhibited EV71 proliferation in HM1900 cells, which are a human microglia cell line, and that LJ04 can directly inactivate EV71 within 2 hr at 37°C. This study demonstrates for the first time the ability of a polysaccharide from L. japonica to inhibit viral and 3C activity; importantly, the inhibition of 3C might have a minor effect on the antiviral effect of LJ04. Consequently, our results identify LJ04 as a potential drug candidate for the control of severe EV71 infection in clinical settings.

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“…Thus, the 69th residue of 3C pro has been identified as a novel virulence determinant of EV-A71 (Li B. et al, 2017 ). Ma et al recently confirmed that the polymorphisms of EV-A71 3C pro at the 79th amino acid position were associated with clinical severity and viral replication, which might be related to the interaction of 3C pro with important host proteins such as tripartite motif-containing protein 21 (TRIM21) (Ma et al, 2017 ). EV-A71 3C pro could interfere with the polyadenylation of host mRNA by digesting the host protein CstF-64, a cleavage-stimulating factor responsible for 3′pre-mRNA cleavage and polyadenylation (Weng et al, 2009 ).…”

Section: Introductionmentioning

confidence: 94%

Enterovirus A71 Proteins: Structure and Function

Yuan

Шен

et al. 2018

Front. Microbiol.

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Enterovirus A71 (EV-A71) infection has grown to become a serious threat to global public health. It is one of the major causes of hand, foot, and mouth disease (HFMD) in infants and young children. EV-A71 can also infect the central nervous system (CNS) and induce diverse neurological complications, such as brainstem encephalitis, aseptic meningitis, and acute flaccid paralysis, or even death. Viral proteins play a crucial role in EV-A71 infection. Many recent studies have discussed the structure and function of EV-A71 proteins, and the findings reported will definitely aid the development of vaccines and therapeutic approaches. This article reviews the progress in the research on the structure and function of EV-A71 proteins. Available literature can provide a basis for studying the pathogenesis of EV-A71 infection in detail.

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Association of EV71 3C polymorphisms with clinical severity

Abstract: We found that 3C polymorphisms were associated with clinical severity and viral replication, which might be related to 3C interaction with important host proteins such as TRIM21.

Cited by 12 publications

References 17 publications

Sequence analysis‐based characterization and identification of neurovirulence‐associated variants of 36 EV71 strains from China

Sequence analysis‐based characterization and identification of neurovirulence‐associated variants of 36 EV71 strains from China

Virucidal activity and the antiviral mechanism of acidic polysaccharides against Enterovirus 71 infectionin vitro

Enterovirus A71 Proteins: Structure and Function

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