Determinants of EV71 immunogenicity and protection against lethal challenge in a mouse model

Chang, Junliang; Li, Jingliang; Wei, Wei; Liu, Xin; Liu, Guanchen; Yang, Jiaxin; Zhang, Wenyan; Yu, Xiao Fang

doi:10.1007/s12026-015-8661-1

Cited by 6 publications

(8 citation statements)

References 40 publications

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“…In theory, preventing viral entry by blocking the “canyon”-receptor interaction would constitute the best way to cure or, at the least, control enteroviral infection. Previous studies have confirmed the role of VP1 variation as a major factor affecting enteroviral immunogenicity [ 9 , 41 ]. In the case of EVD68, the anti-rhinovirus drug pleconaril has already been shown to interact with VP1 and suppress viral pathogenesis in HeLa cells [ 20 ].…”

Section: Discussionmentioning

confidence: 76%

“…Moreover, the identification of the Clade B subclade indicates that such changes can occur very easily, since the four protein variations occurred within just a few years. In addition, we have previously observed that a single amino acid variation in EVA71 VP1 leads to significant differences in the host immune response [ 9 ]. Such occurrences in EVD68 (and probably other enteroviruses as well) poses challenges in the development of antivirals and/or vaccines, the success of which may require the development of novel strategies, such as the design of antiviral drugs that suppress the function of viral protease 3C [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Enterovirus 68 has been classified as a member of group D and thus designated as EVD68. In contrast to other common enteroviruses such as Enterovirus 71 (EVA71) and Coxsackievirus A16 (CV-A16), both of which are categorized as HEV-A and are responsible for the widely spread hand, foot, and mouth disease (HFMD) [ 1 – 9 ], EVD68 causes respiratory illness with mild (sore throat, cough, and fever) to serious (including dyspnea or even respiratory failure) symptoms [ 10 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Enterovirus 68 Strains from the 2014 North American Outbreak Reveals a New Clade, Indicating Viral Evolution

Zheng

et al. 2015

PLoS ONE

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Enterovirus 68 (EVD68) causes respiratory illness, mostly in children. Despite a reported low-level of transmission, the occurrence of several recent outbreaks worldwide including the 2014 outbreak in North America has raised concerns regarding the pathogenesis and evolution of EVD68. To elucidate the phylogenetic features of EVD68 and possible causes for the 2014 outbreak, 216 EVD68 strain sequences were retrieved from Genbank, including 22 from the 2014 outbreak. Several geographic and genotypic origins were established for these 22 strains, 19 of which were classified as Clade B. Of these 19 strains, 17 exhibited subsequent clustering and variation in protein residues involved in host-receptor interaction and/or viral antigenicity. Approximately 18 inter-clade variations were detected in VP1, which led to the identification of a new Clade D in EVD68 strains. The classification of this new clade was also verified by the re-construction of a Neighbor-Joining tree during the phylogenetic analysis. In addition, our results indicate that members of Clade B containing highly specific alterations in VP1 protein residues were the foremost contributors to the 2014 outbreak in the US. Altered host-receptor interaction and/or host immune recognition may explain the evolution of EVD68 as well as the global emergence and ongoing adaptation of this virus.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of Enterovirus 68 Strains from the 2014 North American Outbreak Reveals a New Clade, Indicating Viral Evolution

Zheng

et al. 2015

PLoS ONE

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“…Brain tissue samples (n = 3) were collected 3 and 12 hr after injection from each experimental group. The isolated samples were disrupted and homogenized with the grinding method (Chang et al, 2015). Total tissue RNA was extracted using Trizol reagent (Invitrogen), and viral RNAs in the infected brain tissues were determined by qRT-PCR using EV-D68-specific RNA.…”

Section: Immunoblottingmentioning

confidence: 99%

ICAM-5/Telencephalin Is a Functional Entry Receptor for Enterovirus D68

Wei

Guo

Chang

et al. 2016

Cell Host & Microbe

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Enterovirus D68 (EV-D68) is a member of the Picornaviridae family. Although EV-D68-associated infection was once considered rare, it has been increasing in recent years. EV-D68 infection is most frequently associated with respiratory illness. However, it has also been implicated in a polio-like neurological disorder, acute flaccid myelitis. Although sialic acid has been implicated in EV-D68 entry, the existence of a protein receptor has yet to be clarified. Here we identify neuron-specific intercellular adhesion molecule 5 (ICAM-5/telencephalin) as a cellular receptor for sialic acid-dependent and -independent EV-D68 viruses. EV-D68 bound specifically and efficiently to ICAM-5, and replication of EV-D68 in diverse cell types was inhibited by soluble ICAM-5 fragments. ICAM-5 silencing attenuated EV-D68 replication in permissive cells, and ICAM-5 expression in non-permissive cells allowed EV-D68 replication. The discovery of a neuron-specific adhesion molecule as an EV-D68 receptor has important implications for EV-D68 pathogenesis and may facilitate the development of novel intervention strategies.

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“…In mainland China, Taiwan and Singapore, EV71 whole-virus vaccines have been produced by various manufacturers. Two available inactivated EV71 vaccines have been approved by the China Food and Drug Administration, one produced by Sinovac Biotech Ltd. and the other by the Chinese Academy of Medical Science (all Beijing, China) (8)(9)(10). Currently, no effective treatment is available to treat severe EV71 infections, aside from symptomatic therapies (11).…”

Section: Introductionmentioning

confidence: 99%

Enterovirus 71 infection impairs the reproductive capacity of female mice

Qin

Yan

Chen

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Enterovirus 71 (EV71) is a major cause of hand, foot and mouth disease (HFMD); however, no clinically approved vaccine or antiviral treatment is currently available for EV71 infection. In the present study, a murine model of EV71 infection was constructed. The clinical isolates of EV71 were amplified in Vero cells and used to challenge adult mice via hydrodynamic injection (HI) and intraperitoneal injection (IP). Following two challenges, >50% of the mice succumbed to EV71 infection. Surviving female mice were identified to have impaired fertility and their litter sizes were significantly decreased compared with the control group. The antibody against EV71-VP1 persisted in the sera of female mice at a high titer for >2 years after challenge. The maternal antibody in the offspring sera also persisted for ~1 year and disappeared after ~2 years. Results from the present study suggest that a high titer of active EV71 was able to impair the reproductivity of adult female mice, and that high levels of maternal antibody persisted in the offspring and protected postnatal mice from EV71-induced mortality. The promising antigenicity, immunogenicity and reactogenicity of EV71 suggests that it a potential vaccine target that may be beneficial to the control of HFMD, through immunizing infants and women of reproductive age. IntroductionEnterovirus (EV) 71 is a member of the picornaviridae family of viruses that contain single-stranded positive-sense RNA (1), which primarily infects children <5 years old (2). Infants with EV71 infection develop sores on their hands, feet, buttocks and mouth; therefore, the infection is referred to as hand, foot and mouth disease (HFMD) (3). Several types of enterovirus have been indicated to cause HFMD in children; however, EV71 is commonly associated with severe complications of the nervous system in infants with HFMD and is therefore considered to be a major virulent pathogen and cause of mortalities in HFMD (4). Previous studies have indicated that a total of 488,955 HFMD cases and 126 HFMD-associated mortalities were reported in 2008 in China, of which EV71 infection was the primary cause (5). EV71 is a non-enveloped virus with a single-stranded positive-sense RNA genome that is ~7.5 kb in size and belongs to the enterovirus genus of the picornaviridae family (6). EV71 is classified into five genotypes as follows: A, B, C, D and F, and further subdivided into B0-B5 and C1-C5 subgenotypes (7). HFMD is an important public health issue and further understanding of the mechanisms underlying the development of HFMD are required to develop effective treatments. In mainland China, Taiwan and Singapore, EV71 whole-virus vaccines have been produced by various manufacturers. Two available inactivated EV71 vaccines have been approved by the China Food and Drug Administration, one produced by Sinovac Biotech Ltd. and the other by the Chinese Academy of Medical Science (all Beijing, China) (8-10). Currently, no effective treatment is available to treat severe EV71 infections, aside from symp...

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Determinants of EV71 immunogenicity and protection against lethal challenge in a mouse model

Cited by 6 publications

References 40 publications

Analysis of Enterovirus 68 Strains from the 2014 North American Outbreak Reveals a New Clade, Indicating Viral Evolution

Analysis of Enterovirus 68 Strains from the 2014 North American Outbreak Reveals a New Clade, Indicating Viral Evolution

ICAM-5/Telencephalin Is a Functional Entry Receptor for Enterovirus D68

Enterovirus 71 infection impairs the reproductive capacity of female mice

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