A novel finding for enterovirus virulence from the capsid protein VP1 of EV71 circulating in mainland China

Liu, Yongjuan; Fu, Chong Yau; Su-ying, WU; Chen, Xiong; Shi, Yingying; Zhou, Benhong; Zhang, Lianglu; Zhang, Fengfeng; Wang, Wenwen; Zhang, Yingying; Fan, Chengpeng; Han, Song; Yin, Jun; Peng, Biwen; Liu, Wanhong; He, Xiaohua

doi:10.1007/s11262-014-1035-2

Cited by 53 publications

(36 citation statements)

References 48 publications

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“…The vertex of the 5-fold axis of EV71 plays an important role in not only viral entry but also viral pathogenicity. Molecular epidemiological studies have suggested that VP1-98K and VP1-145G/Q isolates are more frequently detected in cases with severe neurological disease in humans than are VP1-98E and VP1-145E isolates, respectively (41,42). However, on the other hand, substitution of VP1-145G/Q for VP1-145E was found to be responsible for adaptation and/or virulence in both murine and primate models, either alone or in combination with other amino acids (43)(44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Inhibition of the Infectivity of Human Enterovirus 71 by a Sulfonated Food Azo Dye, Brilliant Black BN

Meng

Jia

Wong

et al. 2019

J Virol

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Hand, foot, and mouth disease (HFMD), a highly contagious disease in children, is caused by human enteroviruses, including enterovirus 71 (EV71), coxsackievirus A16 (CVA16), and coxsackievirus A6 (CVA6). Although HFMD is usually mild and self-limiting, EV71 infection occasionally leads to fatal neurological disorders. Currently, no commercial antiviral drugs for HFMD treatment are available. Here, numerous sulfonated azo dyes, widely used as food additives, were identified as having potent antiviral activities against human enteroviruses. Among them, brilliant black BN (E151) was able to inhibit all EV71, CVA16, and CVA6 strains tested. In rhabdomyosarcoma cells, the 50% inhibitory concentrations of the dye E151 for various strains of EV71 ranged from 2.39 M to 28.12 M, whereas its 50% cytotoxic concentration was 1,870 M. Food azo dyes, including E151, interacted with the vertex of the 5-fold axis of EV71 and prevented viral entry. Their efficacy in viral inhibition was regulated by amino acids at VP1-98, VP1-145, and/or VP1-246. Dye E151 not only prevented EV71 attachment but also eluted attached viruses in a concentration-dependent manner. Moreover, E151 inhibited the interaction between EV71 and its cellular uncoating factor cyclophilin A. In vivo studies demonstrated that E151 at a dose of 200 mg/kg of body weight/day given on the initial 4 days of challenge protected AG129 mice challenged with 10ϫ the 50% lethal dose of wild-type EV71 isolates. Taken together, these data highlight E151 as a promising antiviral agent against EV71 infection. IMPORTANCE Human enterovirus 71 (EV71) is one of the causative agents of hand, foot, and mouth disease in children and is responsible for thousands of deaths in the past 20 years. Food azo dyes have been widely used since the nineteenth century; however, their biological effects on humans and microbes residing in humans are poorly understood. Here, we discovered that one of these dyes, brilliant black BN (E151), was particularly effective in inhibiting the infectivity of EV71 in both cell culture and mouse model studies. Mechanistic studies demonstrated that these sulfonated dyes mainly competed with EV71 attachment factors for viral binding to block viral attachment/entry to host cells. As no commercial antiviral drugs against EV71 are currently available, our findings open an avenue to exploit the development of permitted food dye E151 as a potential anti-EV71 agent. KEYWORDS AG129 mouse, antiviral agent, food azo dye, hand foot and mouth disease, human enterovirus, sulfonate, virus attachment factors, virus entry H and, foot and mouth disease (HFMD), a common and highly contagious disease in children, is caused by human enteroviruses, including enterovirus 71 (EV71), coxsackievirus A16 (CVA16), and coxsackievirus A6 (CVA6). The clinical features of HFMD include rashes on the hands and feet, buccal ulcerative lesions, fatigue, fever, RESULTSInhibitory effects of food dyes on the propagation of EV71-GFP. Eleven widely used food dyes were screened for their potency in inhi...

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Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Inhibition of the Infectivity of Human Enterovirus 71 by a Sulfonated Food Azo Dye, Brilliant Black BN

Meng

Jia

Wong

et al. 2019

J Virol

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“…Additionally, the viral factors associated with severe clinical outcome remain unclarified. To date, some groups have argued that the amino acid substitutions in capsid protein VP1 of EV‐A71 strains might contribute to the different severity of the disease [Liu et al, ]. However, the mechanism for the severity caused by EV‐A71 is quite complex [Lin et al, ; Zhang et al, ].…”

Section: Discussionmentioning

confidence: 99%

Molecular epidemiology of an outbreak of hand, foot, and mouth disease associated with subgenotype C4a of enterovirus A71 in Nanchang, China in 2014

et al. 2015

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An outbreak of hand, foot, and mouth disease was reported through hospital-based surveillance in Nanchang, China in 2014. A total of 244 cases were reported, 176 (72.1%) cases were tested positive for enteroviruses by direct reverse transcription-polymerase chain reaction, in which enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), and untyped enteroviruses (UEV) accounted for 84.1%, 3.4%, and 12.5%, respectively. In this outbreak, children under 5 years old constituted more than 98% of the positive cases, and the ratio of male to female cases was 2.6 to 1 (P < 0.01). Phylogenetic analysis indicated that the Nanchang EV-A71 strains belonged to subgenotype C4a undergoing continuously evolutionary changes.

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“…The results suggested that non-PB strains are mainly responsible for the development of viremia and neuropathogenesis. In humans, VP1-145G or VP1-145Q was isolated more frequently from severely affected patients than from mildly affected patients, although the majority of viruses isolated from both patient types have E at position 145 (24)(25)(26)(27). In the accompanying paper (28), we showed that VP1-145E is more virulent than VP1-145G in an hSCARB2 transgenic (tg) mouse model.…”

mentioning

confidence: 89%

VP1 Amino Acid Residue 145 of Enterovirus 71 Is a Key Residue for Its Receptor Attachment and Resistance to Neutralizing Antibody during Cynomolgus Monkey Infection

Fujii

Sudaka

Takashino

et al. 2018

J Virol

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Enterovirus 71 (EV71) is a causative agent of hand, foot, and mouth disease and sometimes causes severe or fatal neurological complications. The amino acid at VP1-145 determines virological characteristics of EV71. Viruses with glutamic acid (E) at VP1-145 (VP1-145E) are virulent in neonatal mice and transgenic mice expressing human scavenger receptor B2, whereas those with glutamine (Q) or glycine (G) are not. However, the contribution of this variation to pathogenesis in humans is not fully understood. We compared the virulence of VP1-145E and VP1-145G viruses of Isehara and C7/Osaka backgrounds in cynomolgus monkeys. VP1-145E, but not VP1-145G, viruses induced neurological symptoms. VP1-145E viruses were frequently detected in the tissues of infected monkeys. VP1-145G viruses were detected less frequently and disappeared quickly. Instead, mutants that had a G to E mutation at VP1-145 emerged, suggesting that VP1-145E viruses have a replication advantage in the monkeys. This is consistent with our hypothesis proposed in the accompanying paper that the VP1-145G virus is attenuated due to its adsorption by heparan sulfate. Monkeys infected with both viruses produced neutralizing antibodies before the onset of the disease. Interestingly, VP1-145E viruses were more resistant to neutralizing antibodies than VP1-145G viruses A small amount of neutralizing antibody raised in the early phase of infection may not be sufficient to block the dissemination of VP1-145E viruses. The different resistance of the VP1-145 variants to neutralizing antibodies may be one of the reasons for the difference in virulence. The contribution of VP1-145 variants in humans is not fully understood. In some reports, VP1-145G/Q viruses were more frequently isolated from severely affected than from mildly affected patients, suggesting that VP1-145G/Q viruses are more virulent. In the accompanying paper, we showed that VP1-145E viruses are more virulent than VP1-145G viruses in human SCARB2 transgenic mice. Heparan sulfate acts as a decoy to specifically trap the VP1-145G viruses and leads to abortive infection. Here, we demonstrated that VP1-145G was attenuated in cynomolgus monkeys, suggesting that this hypothesis is also true in a non-human primate model. VP1-145E viruses, but not VP1-145G viruses, were highly resistant to neutralizing antibodies. We propose the difference in resistance against neutralizing antibodies as another mechanism of EV71 virulence. In summary, VP1-145 contributes to virulence determination by controlling attachment receptor usage and antibody sensitivity.

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A novel finding for enterovirus virulence from the capsid protein VP1 of EV71 circulating in mainland China

Cited by 53 publications

References 48 publications

In Vitro and In Vivo Inhibition of the Infectivity of Human Enterovirus 71 by a Sulfonated Food Azo Dye, Brilliant Black BN

In Vitro and In Vivo Inhibition of the Infectivity of Human Enterovirus 71 by a Sulfonated Food Azo Dye, Brilliant Black BN

Molecular epidemiology of an outbreak of hand, foot, and mouth disease associated with subgenotype C4a of enterovirus A71 in Nanchang, China in 2014

VP1 Amino Acid Residue 145 of Enterovirus 71 Is a Key Residue for Its Receptor Attachment and Resistance to Neutralizing Antibody during Cynomolgus Monkey Infection

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