Outbreak of severe neurologic involvement associated with enterovirus 71 infection

Komatsu, Hiroshi; Shimizu, Yoshitaka; Takeuchi, Yoshihiro; Ishiko, Hiroaki; Takada, Hiroshi

doi:10.1016/s0887-8994(98)00087-3

Cited by 125 publications

(88 citation statements)

References 18 publications

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“…Interestingly, studies indicate that PV1 and EV71 viruses with a mutation in the 5Ј NTR [PV1 (Sabin) and EV71(S1-3Ј)] are fairly stable in the lumbar spinal cord of inoculated monkeys (5,24). The lesions of the brain stem are critical causes of fatality from EV71 infection (10,21,25,31,57), suggesting that the introduced attenuation determinant of PV1(Sabin) contributes to EV71-specific pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

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An Attenuated Strain of Enterovirus 71 Belonging to Genotype A Showed a Broad Spectrum of Antigenicity with Attenuated Neurovirulence in Cynomolgus Monkeys

Arita¹,

Nagata²,

Iwata³

et al. 2007

J Virol

123

100

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Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and is also sometimes associated with serious neurological disorders. In this study, we characterized the antigenicity and tissue specificity of an attenuated strain of EV71 [EV71(S1-3)], which belongs to genotype A, in a monkey infection model. Three cynomolgus monkeys were inoculated with EV71(S1-3), followed by lethal challenge with the parental virulent strain EV71(BrCr-TR) via an intravenous route on day 45 postinoculation of EV71(S1-3). Monkeys inoculated with EV71(S1-3) showed a mild neurological symptom (tremor) but survived lethal challenge by virulent EV71(BrCr-TR) without exacerbation of the symptom. The immunized monkey sera showed a broad spectrum of neutralizing activity against different genotypes of EV71, including genotypes A, B1, B4, C2, and C4. For the strains examined, the sera showed the highest neutralization activity against the homotype (genotype A) and the lowest neutralization activity against genotype C2. The order of decreasing neutralization activity of sera was as follows: A > B1 > C4 > B4 > C2. To examine the tissue specificity of EV71(S1-3), two monkeys were intravenously inoculated with EV71(S1-3), followed by examination of virus distribution in the central nervous system (CNS) and extraneural tissues. In the CNS, EV71(S1-3) was isolated only from the spinal cord. These results indicate that EV71(S1-3) acts as an effective antigen, although this attenuated strain was still neurotropic when inoculated via the intravenous route.Enterovirus 71 (EV71) is a small nonenveloped virus with a genome of single-strand positive RNA of about 7,500 nucleotides and belongs to the genus Enterovirus of the family Picornaviridae (8, 48). EV71 is classified as Human enterovirus species A along with some coxsackie A (CA) viruses, such as CA10 and CA16 (8, 44). CA10, CA16, and EV71 cause hand, foot, and mouth disease (HFMD) and herpangina. EV71 infection is also sometimes associated with severe neurological diseases, such as brain stem encephalitis and poliomyelitis-like paralysis, mainly in infants and young children (11,34,56). The neuropathogenic features of EV71 were first emphasized during an outbreak in Bulgaria in 1975 in which poliomyelitis-like paralysis was the major symptom (21.1% of patients), with a high fatality rate (29.5%) among the paralytic cases (51). In recent large-scale outbreaks of HFMD in Malaysia (1997) (1, 50) and Taiwan (1998 and2000) (20,28,29,55), several fatal encephalitis cases were reported. In the EV71 outbreak in Taiwan in 1998, out of 129,106 cases of HFMD or herpangina, there were 405 severe cases, including 78 fatal cases (20); thus, the severity rate of this outbreak was Ͻ0.3%. These findings underscore the high neuropathogenicity of EV71 as well as poliovirus (PV), which causes poliomyelitis in 0.1 to 1.0% of infected individuals (reviewed in reference 36).Most of the fatal EV71 cases in Taiwan were in young children (age, Յ5 years) and involved pulmonary edema and/or pulmonary hemorrha...

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Section: Discussionmentioning

confidence: 99%

“…These symptoms were of neurogenic origin, and brain stem involvement (direct destruction of the vasomotor and respiratory centers) was critical (10,21,25,31,57). Disseminated infection of EV71 in the central nervous system (CNS) might in part explain the EV71-specific neuropathogenesis (40).…”

mentioning

confidence: 99%

An Attenuated Strain of Enterovirus 71 Belonging to Genotype A Showed a Broad Spectrum of Antigenicity with Attenuated Neurovirulence in Cynomolgus Monkeys

Arita¹,

Nagata²,

Iwata³

et al. 2007

J Virol

123

100

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“…However, large HFMD epidemics with high mortality rates resurfaced 2 decades later, in Malaysia in 1997 (2,13,16,43) and Taiwan in 1998 (33,42). Following these outbreaks, the Asia-Pacific region has experienced more frequent large-scale EV-71-associated HFMD epidemics-most with a high incidence of neurotropic infections and significant case fatality rates-and the virus has attracted global attention (3,5,14,15,18,37,46,48,55,57,74,81,82). Intriguingly, almost all outbreaks reported in the AsiaPacific region during the last decade were caused by previously undefined EV-71 subgenogroups, raising questions about their origin, genetic complexity, and epidemiological behavior.…”

Section: Human Enterovirus 71 (Ev-71) Is One Of the Major Etiologic Cmentioning

confidence: 99%

Evolutionary Genetics of Human Enterovirus 71: Origin, Population Dynamics, Natural Selection, and Seasonal Periodicity of the VP1 Gene

Tee

Lam

Chan

et al. 2010

J Virol

202

195

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Human enterovirus 71 (EV-71) is one of the major etiologic causes of hand, foot, and mouth disease (HFMD) among young children worldwide, with fatal instances of neurological complications becoming increasingly common. Global VP1 capsid sequences (n ‫؍‬ 628) sampled over 4 decades were collected and subjected to comprehensive evolutionary analysis using a suite of phylogenetic and population genetic methods. We

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“…The case-severity rate of EV71 in an outbreak in Taiwan was ,0.3 % (Ho et al, 1999), suggesting a high neuropathogenicity of EV71 as well as PV, which causes poliomyelitis in 0.1-1.0 % of infected individuals (reviewed by Minor, 1992). EV71 causes fatal pulmonary oedema and/or pulmonary haemorrhage in young children by destruction of the vasomotor and respiratory centres in the brain stem Ho et al, 1999;Huang et al, 1999;Komatsu et al, 1999;Lum et al, 1998;Wang et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Characterization of pharmacologically active compounds that inhibit poliovirus and enterovirus 71 infectivity

Arita

Wakita

Shimizu

2008

Journal of General Virology

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Poliovirus (PV) and enterovirus 71 (EV71) cause severe neurological symptoms in their infections of the central nervous system. To identify compounds with anti-PV and anti-EV71 activities that would not allow the emergence of resistant mutants, we performed drug screening by utilizing a pharmacologically active compound library targeting cellular factors with PV and EV71 pseudoviruses that encapsidated luciferase-encoding replicons. We have found that metrifudil (N-[2-methylphenyl]methyl)-adenosine) (an A2 adenosine receptor agonist), N 6 -benzyladenosine (an A1 adenosine receptor agonist) and NF449 (4,49,40,409-[carbonylbis[imino-5,1,3-benzenetriyl bis(carbonyl-imino)]] tetrakis (benzene-1,3-disulfonic acid) octasodium salt) (a Gs-a inhibitor) have anti-EV71 activity, and that GW5074 (3-(3, 5-dibromo-4-hydroxybenzylidine-5-iodo-1,3-dihydro-indol-2-one)) (a Raf-1 inhibitor) has both anti-PV and anti-EV71 activities. EV71 mutants resistant to metrifudil, N 6 -benzyladenosine and NF449 were isolated after passages in the presence of these compounds, but mutants resistant to GW5074 were not isolated for both PV and EV71. The inhibitory effect of GW5074 was not observed in Sendai virus infection and the treatment did not induce the expression of OAS1 and STAT1 mRNA. Small interfering RNA treatment against putative cellular targets of GW5074, including Raf-1, B-Raf, Pim-1, -2, and -3, HIPK2, GAK, MST2 and ATF-3, did not consistently suppress PV replication. Moreover, downregulation of Raf-1 and B-Raf did not affect the sensitivity of RD cells to the inhibitory effect of GW5074. These results suggest that GW5074 has strong and selective inhibitory effect against the replication of PV and EV71 by inhibiting conserved targets in the infection independently of the interferon response.

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Outbreak of severe neurologic involvement associated with enterovirus 71 infection

Cited by 125 publications

References 18 publications

An Attenuated Strain of Enterovirus 71 Belonging to Genotype A Showed a Broad Spectrum of Antigenicity with Attenuated Neurovirulence in Cynomolgus Monkeys

An Attenuated Strain of Enterovirus 71 Belonging to Genotype A Showed a Broad Spectrum of Antigenicity with Attenuated Neurovirulence in Cynomolgus Monkeys

Evolutionary Genetics of Human Enterovirus 71: Origin, Population Dynamics, Natural Selection, and Seasonal Periodicity of the VP1 Gene

Characterization of pharmacologically active compounds that inhibit poliovirus and enterovirus 71 infectivity

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