Protection of neonatal mice from lethal enterovirus 71 infection by maternal immunization with attenuated Salmonella enterica serovar Typhimurium expressing VP1 of enterovirus 71

Chiu, Cheng Hsun; Chu, Chishih; He, Chao; Lin, Tzou Yien

doi:10.1016/j.micinf.2006.01.021

Cited by 76 publications

(52 citation statements)

References 27 publications

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“…However, there is no effective therapy for vaccineassociated paralytic poliomyelitis, which is caused by virulent revertants of vaccine strains at a rate of one case per 520 000 doses associated with the first dose of the vaccine (Nkowane et al, 1987). For EV71, various vaccine candidates and therapies are being developed, but no vaccine has been established (Chen et al, 2006;Chiu et al, 2006;Liu et al, 2005Liu et al, , 2007Shih et al, 2004;Tan & Cardosa, 2007;Tung et al, 2007;Wu et al, 2007;Yu et al, 2000). The results obtained in this study would be useful for the identification of novel targets to develop antienterovirus drugs that could serve as therapeutic and/or prophylactic agents against acute neurological diseases caused by enterovirus infection.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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Section: Introductionmentioning

confidence: 99%

“…However, there is no effective therapeutic means for vaccine-associated paralytic poliomyelitis caused by virulent revertants of vaccine strains, which occurred at a rate of one case per 520 000 vaccinations with the first dose of the live-attenuated vaccine (Nkowane et al, 1987). For EV71, various vaccine candidates and therapeutic means are being developed, but no vaccine has been established (Arita et al, 2005a(Arita et al, , 2007Chen et al, 2006;Chiu et al, 2006;Liu et al, 2005Liu et al, , 2007 Shih et al, 2004;Tan & Cardosa, 2007;Tung et al, 2007;Wu et al, 2007; Yu et al, 2000).To date, several anti-enterovirus compounds that target cellular factors and inhibit various stages of virus replication have been identified. Brefeldin A blocks membrane traffic between the cis-and trans-Golgi compartments by targeting a cellular guanine nucleotide- exchange factor, GBF1, and inhibits the replication of PV, but not encephalomyocarditis virus (EMCV) (Belov et al, 2008;Cuconati et al, 1998;Irurzun et al, 1992;Maynell et al, 1992).…”

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confidence: 99%

Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime

Arita

Wakita

Shimizu

2009

Journal of General Virology

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Previously, we identified a cellular kinase inhibitor, GW5074, that inhibits poliovirus (PV) and enterovirus 71 replication strongly, although its target has remained unknown. To identify the target of GW5074, we searched for cellular kinase inhibitors that have anti-enterovirus activity similar or related to that of GW5074. With this aim, we performed screenings to identify cellular kinase inhibitors that could inhibit PV replication cooperatively with GW5074 or synthetically in the absence of GW5074. We identified MEK1/2 inhibitors (SL327 and U0126), an EGFR inhibitor (AG1478) and a phosphatidylinositol 3-kinase inhibitor (wortmannin) as compounds with a cooperative inhibitory effect with GW5074, and an Akt1/2 inhibitor (Akt inhibitor VIII) as a compound with a synthetic inhibitory effect with MEK1/2 inhibitors and AG1478. Individual treatment with the identified kinase inhibitors did not affect PV replication significantly, but combined treatment with MEK1/2 inhibitor, AG1478 and Akt1/2 inhibitor suppressed the replication synthetically. The effect of AG1478 in this synthetic inhibition was compensated by other receptor tyrosine kinase inhibitors (IGF-1R inhibitor II and Flt3 inhibitor II). We isolated mutants resistant to Flt3 inhibitor II and GW5074 and found that these mutants had crossresistance to each treatment. These mutants had a common mutation in viral protein 3A that results in an amino acid change at position 70 (Ala to Thr), a mutation that was previously identified in mutants resistant to a potent anti-enterovirus compound, enviroxime. These results suggest that cellular kinase inhibitors and enviroxime have a conserved target in viral protein 3A to suppress enterovirus replication. INTRODUCTIONThe genus Enterovirus consists of at least ten species of non-enveloped viruses with a single-stranded, positivesense genomic RNA that belong to the family Picornaviridae. Enterovirus infection is mostly asymptomatic, but sometimes causes severe neurological symptoms exemplified by poliomyelitis. In infection by poliovirus (PV), which is the causative agent of poliomyelitis and belongs to the species Human enterovirus C, motor neurons are the major target for neurovirulence (Bodian, 1949). Enterovirus 71 (EV71), another neurotropic enterovirus belonging to the species Human enterovirus A, is a causative agent of hand, foot and mouth disease and herpangina, but sometimes causes severe neurological diseases, such as brainstem encephalitis and poliomyelitis-like paralysis (Chumakov et al., 1979;McMinn, 2002;Wang et al., 2003). EV71 causes fatal pulmonary oedema and pulmonary haemorrhage in young children by destruction of the vasomotor and respiratory centres in the brainstem Ho et al., 1999;Huang et al., 1999;Komatsu et al., 1999;Lum et al., 1998;Wang et al., 1999). For PV, live-attenuated and inactivated vaccines have been established and are currently being used for global eradication of poliomyelitis (Sabin, 1965;Salk et al., 1954). However, there is no effective therapeutic means for vaccine-associated...

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“…This suggests a high neuropathogenicity of EV71 similar to that of poliovirus (PV), which causes poliomyelitis in 0.1 to 1.0% of infected individuals (reviewed in reference 46). Currently, various vaccines and treatments against EV71 infection are being developed (13,15,38,39,61,64,66,72,73).Experimental infection models of EV71 have been established in the monkey and mouse (14,21,22,49,50,71). The advantage of the monkey model is that the monkeys inoculated with clinical isolates of EV71 show neurological disorders similar to those observed in human cases of EV71 infection, including tremor, ataxia, and poliomyelitis-like paralysis; these disorders are critical for the evaluation of the neurovirulence of EV71 strains (3, 5).…”

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confidence: 99%

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confidence: 99%

Cooperative Effect of the Attenuation Determinants Derived from Poliovirus Sabin 1 Strain Is Essential for Attenuation of Enterovirus 71 in the NOD/SCID Mouse Infection Model

Arita¹,

Ami

Wakita³

et al. 2008

J Virol

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Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and is also associated with serious neurological disorders. An attenuated EV71 strain [EV71(S1-3)] has been established in the cynomolgus monkey infection model; this strain contains the attenuation determinants derived from the type 1 poliovirus vaccine strain, Sabin 1 [PV1(Sabin)], in the 5 nontranslated region (NTR), 3D polymerase, and 3 NTR. In this study, we analyzed the effect of the attenuation determinants of PV1(Sabin) on EV71 infection in a NOD/SCID mouse infection model. We isolated a mouse-adapted EV71 strain [EV71(NOD/SCID)] that causes paralysis of the hind limbs in 3-to 4-week-old NOD/SCID mice by adaptation of the virulent EV71(Nagoya) strain in the brains of NOD/SCID mice. A single mutation at nucleotide 2876 that caused an amino acid change in capsid protein VP1 (change of the glycine at position 145 to glutamic acid) was essential for the mouse-adapted phenotype in NOD/SCID mice. Next, we introduced attenuation determinants derived from PV1(Sabin) along with the mouse adaptation mutation into the EV71(Nagoya) genome. In 4-week-old mice, the determinants in the 3D polymerase and 3 NTR, which are the major temperature-sensitive determinants, had a strong effect on attenuation. In contrast, the effect of individual determinants was weak in 3-week-old NOD/SCID mice, and all the determinants were required for substantial attenuation. These results suggest that a cooperative effect of the attenuation determinants of PV1(Sabin) is essential for attenuated neurovirulence of EV71.Enterovirus 71 (EV71) is a small nonenveloped virus with a genome of single-strand positive RNA of about 7,500 nucleotides (nt); it belongs to the genus Enterovirus of the family Picornaviridae (10, 60). EV71 is classified as Human enterovirus species A, along with some coxsackie A viruses, such as CA10 and CA16, which cause hand, foot, and mouth disease and herpangina (10, 54). However, EV71 infection is sometimes associated with severe neurological diseases, such as brain stem encephalitis and poliomyelitis-like paralysis (16,44,69). Fatal effects of an EV71 outbreak in Taiwan were mostly due to pulmonary edema and/or pulmonary hemorrhage, which may have been caused by direct destruction of the vasomotor and respiratory centers in the brain stem by EV71 infection (11,23,25,36,40,70). The case severity rate of EV71 in the outbreak was Ͻ0.3% (23). This suggests a high neuropathogenicity of EV71 similar to that of poliovirus (PV), which causes poliomyelitis in 0.1 to 1.0% of infected individuals (reviewed in reference 46). Currently, various vaccines and treatments against EV71 infection are being developed (13,15,38,39,61,64,66,72,73).Experimental infection models of EV71 have been established in the monkey and mouse (14,21,22,49,50,71). The advantage of the monkey model is that the monkeys inoculated with clinical isolates of EV71 show neurological disorders similar to those observed in human cases of EV71 infection, including tremor, ataxia, and poli...

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Protection of neonatal mice from lethal enterovirus 71 infection by maternal immunization with attenuated Salmonella enterica serovar Typhimurium expressing VP1 of enterovirus 71

Cited by 76 publications

References 27 publications

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

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

Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime

Cooperative Effect of the Attenuation Determinants Derived from Poliovirus Sabin 1 Strain Is Essential for Attenuation of Enterovirus 71 in the NOD/SCID Mouse Infection Model

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