Oral immunization of mice using transgenic tomato fruit expressing VP1 protein from enterovirus 71

Chen, Hsuan-Fu; Chang, Meng-Huei; Chiang, Bor‐Luen; Jeng, Shih‐Tong

doi:10.1016/j.vaccine.2005.12.047

Cited by 104 publications

(67 citation statements)

References 34 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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“…Inactivated wholevirus and recombinant EV71 virus-like particles (VLPs) containing all capsid subunit proteins could elicit potent neutralizing antibodies (reviewed in references 4 and 5). Besides intact capsids, VP1 has been shown to be the main protein subunit capable of inducing neutralizing antibodies (7)(8)(9) and thus contain neutralizing epitopes. Indeed, two linear neutralizing epitopes, namely, SP70 and SP55, have been identified within VP1 (10).…”

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confidence: 99%

Chimeric Virus-Like Particle Vaccines Displaying Conserved Enterovirus 71 Epitopes Elicit Protective Neutralizing Antibodies in Mice through Divergent Mechanisms

et al. 2014

J Virol

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Enterovirus 71 (EV71) is a major causative agent of hand, food, and mouth disease, which frequently occurs in young children. Since there are 11 subgenotypes (A, B1 to B5, and C1 to C5) within EV71, an EV71 vaccine capable of protecting against all of these subgenotypes is desirable. We report here the vaccine potential and protective mechanism of two chimeric virus-like particles (VLPs) presenting conserved neutralizing epitopes of EV71. We show that fusions of hepatitis B core antigen (HBc) with the SP55 or SP70 epitope of EV71, designated HBcSP55 and HBcSP70, respectively, can be rapidly generated and self-assembled into VLPs with the epitopes displayed on the surface. Immunization with the chimeric VLPs induced carrier-and epitope-specific antibody responses in mice. Anti-HBcSP55 and anti-HBcSP70 sera, but not anti-HBc sera, were able to neutralize in vitro multiple genotypes and strains of EV71. Importantly, passive immunization with anti-HBcSP55 or anti-HBcSP70 sera protected neonatal mice against lethal EV71 infections. Interestingly, anti-HBcSP70 sera could inhibit EV71 attachment to susceptible cells, whereas anti-HBcSP55 sera could not. However, both antisera were able to neutralize EV71 infection in vitro at the postattachment stage. The divergent mechanism of neutralization and protection conferred by anti-SP70 and anti-SP55 sera is in part attributed to their respective ability to bind authentic viral particles. Collectively, our study not only demonstrates that chimeric VLPs displaying the SP55 and SP70 epitopes are promising candidates for a broad-spectrum EV71 vaccine but also reveals distinct mechanisms of neutralization by the SP55-and SP70-targeted antibodies. E nterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease, which is prevalent in the Asia-Pacific region. EV71 infection may result in severe neurological complications and even death (1-3). However, there is currently no available EV71 vaccine (4, 5).EV71 is a member of the enterovirus genus of the Picornaviridae family. It possesses a single-stranded, positive-sense RNA genome, which is encapsidated within an icosahedral capsid consisting of 60 copies of each of VP1, VP2, VP3, and VP4 subunit proteins. Based on the VP1 sequence, EV71 is categorized into three genotypes (A, B, and C), which can be further divided into eleven subgenotypes (A, B1 to B5, and C1 to C5) (reviewed in references 1 and 2). Thus, an EV71 vaccine capable of protecting against all of these subgenotypes is desirable.Increasing evidence has established that neutralizing antibodies play a key role in in vivo protection against lethal EV71 infection (reviewed in references 4 and 5). For example, Foo et al. showed that passive transfer of neutralizing antisera protects recipient mice against lethal EV71 challenge (6). Inactivated wholevirus and recombinant EV71 virus-like particles (VLPs) containing all capsid subunit proteins could elicit potent neutralizing antibodies (reviewed in references 4 and 5). Besides intact capsids, VP1 has been sh...

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Oral immunization of mice using transgenic tomato fruit expressing VP1 protein from enterovirus 71

Cited by 104 publications

References 34 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

Chimeric Virus-Like Particle Vaccines Displaying Conserved Enterovirus 71 Epitopes Elicit Protective Neutralizing Antibodies in Mice through Divergent Mechanisms

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