Enterovirus 68 in Children with Acute Respiratory Tract Infections, Osaka, Japan

Kaida, Atsushi; Kubo, Hideyuki; Sekiguchi, Jun‐ichiro; Kohdera, Urara; Togawa, Masao; Shiomi, Masashi; Nishigaki, Toshinori; Iritani, Nobuhiro

doi:10.3201/eid1708.110028

Cited by 63 publications

(95 citation statements)

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“…We further defined subclades A1, A2, B1, and B2. In line with our subclade definition, subclades A1 and B2 were endemic and found in many countries before the (16,19,30). During the 2014 outbreak, a novel subclade, B1, seems to have rapidly emerged and was dominant during the U.S. outbreak (38,60,61).…”

Section: Discussionmentioning

confidence: 65%

“…Our phylogenetic analyses are notable in that they suggest a relatively complex molecular evolution of EV-D68 during the 2014 outbreak. Before this outbreak, EV-D68 was rarely reported and was associated with mild respiratory illness, although small outbreaks had been documented since 2005 (15,16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). Previous studies showed that the A, B, and C clades circulated or cocirculated during different time periods in different geographic regions (15,16,18,19,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)59).…”

Section: Discussionmentioning

confidence: 99%

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Molecular Evolution and Intraclade Recombination of Enterovirus D68 during the 2014 Outbreak in the United States

Tan

Hassan

Schuster

et al. 2016

J Virol

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In August 2014, an outbreak of enterovirus D68 (EV-D68) occurred in North America, causing severe respiratory disease in children. Due to a lack of complete genome sequence data, there is only a limited understanding of the molecular evolution and epidemiology of EV-D68 during this outbreak, and it is uncertain whether the differing clinical manifestations of EV-D68 infection are associated with specific viral lineages. We developed a high-throughput complete genome sequencing pipeline for EV-D68 that produced a total of 59 complete genomes from respiratory samples with a 95% success rate, including 57 genomes from Kansas City, MO, collected during the 2014 outbreak. With these data in hand, we performed phylogenetic analyses of complete genome and VP1 capsid protein sequences. Notably, we observed considerable genetic diversity among EV-D68 isolates in Kansas City, manifest as phylogenetically distinct lineages, indicative of multiple introductions of this virus into the city. In addition, we identified an intersubclade recombination event within EV-D68, the first recombinant in this virus reported to date. Finally, we found no significant association between EV-D68 genetic variation, either lineages or individual mutations, and a variety of demographic and clinical variables, suggesting that host factors likely play a major role in determining disease severity. Overall, our study revealed the complex pattern of viral evolution within a single geographic locality during a single outbreak, which has implications for the design of effective intervention and prevention strategies. IMPORTANCEUntil recently, EV-D68 was considered to be an uncommon human pathogen, associated with mild respiratory illness. However, in 2014 EV-D68 was responsible for more than 1,000 disease cases in North America, including severe respiratory illness in children and acute flaccid myelitis, raising concerns about its potential impact on public health. Despite the emergence of EV-D68, a lack of full-length genome sequences means that little is known about the molecular evolution of this virus within a single geographic locality during a single outbreak. Here, we doubled the number of publicly available complete genome sequences of EV-D68 by performing high-throughput next-generation sequencing, characterized the evolutionary history of this outbreak in detail, identified a recombination event, and investigated whether there was any correlation between the demographic and clinical characteristics of the patients and the viral variant that infected them. Overall, these results will help inform the design of intervention strategies for EV-D68.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Molecular Evolution and Intraclade Recombination of Enterovirus D68 during the 2014 Outbreak in the United States

Tan

Hassan

Schuster

et al. 2016

J Virol

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“…Over the past 3 years, outbreaks in Japan, the Philippines, and the Netherlands as well as epidemic clusters in the United Kingdom have implicated HEV-D68 as an emerging respiratory pathogen (2, 4-9). The clinical presentation of HEV-D68 infections during these outbreaks ranged from mild illness to rare severe pneumonia cases requiring admission in intensive care units (2,(4)(5)(6)(7)(8)(9). Among these epidemic strains, novel genetic variants were described (2, 4-8).…”

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confidence: 99%

Enterovirus 68 in Pediatric Patients Hospitalized for Acute Airway Diseases

Renois¹,

Bouin²,

Andréoletti³

2013

J Clin Microbiol

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Enterovirus 68 was detected in 10 respiratory specimens from pediatric patients hospitalized for acute wheezing or bronchitis during 2009 in the northeast of France. Viral loads ranged from 2 ؋ 10 5 to 7.2 ؋ 10 7 copies/ml. Alignment of 5= nontranslated regions and phylogenetic analysis of partial VP1 gene sequences show that these viruses clustered and belonged to clade C. Human enterovirus 68 (HEV-D68) was isolated from respiratory specimens for the first time in 1962 in the United States in children with pneumonia and bronchiolitis (1). Unlike other enteroviruses, HEV-D68 is acid labile and biologically more similar to human rhinoviruses in being mainly associated with respiratory diseases; however, until recently, reports of respiratory infections due to HEV-D68 were rare (2, 3). Over the past 3 years, outbreaks in Japan, the Philippines, and the Netherlands as well as epidemic clusters in the United Kingdom have implicated HEV-D68 as an emerging respiratory pathogen (2, 4-9). The clinical presentation of HEV-D68 infections during these outbreaks ranged from mild illness to rare severe pneumonia cases requiring admission in intensive care units (2,(4)(5)(6)(7)(8)(9). Among these epidemic strains, novel genetic variants were described (2, 4-8). The present classical enterovirus molecular assays used in routine virological diagnosis can fail to detect HEV-D68 strains in respiratory samples, leading to an underestimation of the prevalence and the role of HEV-D68 infections in pediatric acute airway diseases (10). We report here the phylogenetic characterization of HEV-D68 strains detected in a cohort of pediatric patients hospitalized for acute airway diseases.The study. Total nucleic acid extraction was performed using the NucliSens EasyMAG instrument (bioMérieux, Lyon, France), according to the manufacturer's instructions. A quantitative realtime reverse transcription (RT)-PCR targeting the 5= nontranslated region (5=NTR) of the Enterovirus genus (EV; including enteroviruses HEV A to D and rhinoviruses HRV A to C) was carried out to perform a pan-enterovirus and rhinovirus detection and to quantify the viral load. Briefly, 2 l total nucleic acid extract was amplified in a 10-l RT-PCR mixture containing 5 l 2ϫ reaction mix, 2 U SuperScript III RT/Platinum Taq mix (Invitrogen, Life Technologies, Saint-Aubin, France), and 0.4 M each primer and probe. The primer sequences used were 5=-AGCCTG CGTGGCKGCC-3= and 5=-GAAACACGGACACCCAAAG-3=, and the probe was 5=-6-carboxyfluorescein (FAM)-CTCCGGCC CCTGAATGYGGCTAA-3= (10). The cycling conditions included initial incubations at 55°C for 30 min and 94°C for 2 min, followed by 40 cycles of 94°C for 15 s and 63°C for 1 min. Full-length CVB3-Nancy RNA transcripts containing the target sequences were synthesized and used as a positive control for copy number calculation. Sensitivity of the PCR assay was estimated to 100 copies per PCR well reaction by 10-fold serial limit dilutions of these RNA transcripts (11).To discriminate HEV from HRV strains, we performed a specific HEV...

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“…A global upsurge of EV-D68 infections in patients with respiratory tract infections (RTIs) has been observed in recent years (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). In 2014, a large outbreak of EV-D68 infections occurred in the United States, which raised public health concern owing to severe respiratory illness and neurological complications (22)(23)(24)(25)(26)(27)(28)(29)(30).…”

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confidence: 99%

3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7

Zou

Liu

Lei

et al. 2016

J Virol

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Human enterovirus 68 (EV-D68) is a member of the EV-D species, which belongs to the EV genus of the Picornaviridae family.Over the past several years, clusters of EV-D68 infections have occurred worldwide. A recent outbreak in the United States is the largest one associated with severe respiratory illness and neurological complication. Although clinical symptoms are recognized, the virus remains poorly understood. Here we report that EV-D68 inhibits innate antiviral immunity by downregulation of interferon regulatory factor 7 (IRF7), an immune factor with a pivotal role in viral pathogenesis. This process depends on 3C pro , an EV-D68-encoded protease, to mediate IRF7 cleavage. When expressed in host cells, 3C pro targets Q167 and Q189 within the constitutive activation domain, resulting in cleavage of IRF7. Accordingly, wild-type IRF7 is fully active. However, IRF7 cleavage abrogated its capacity to activate type I interferon expression and limit replication of EV-D68. Notably, IRF7 cleavage strictly requires the protease activity of 3C pro . Together, these results suggest that a dynamic interplay between 3C pro and IRF7 may determine the outcome of EV-D68 infection. IMPORTANCE EV-D68 is a globally emerging pathogen, but the molecular basis of EV-D68 pathogenesis is unclear. Here we report that EV-D68 inhibits innate immune responses by targeting an immune factor, IRF7. This involves the 3C protease encoded by EV-D68, which mediates the cleavage of IRF7. These observations suggest that the 3C pro -IRF7 interaction may represent an interface that dictates EV-D68 infection.E nterovirus D68 (EV-D68) was first isolated from children with lower respiratory tract infections in California, USA, in 1962 and belongs to the species Enterovirus D within the Enterovirus genus, Picornaviridae (1). A global upsurge of EV-D68 infections in patients with respiratory tract infections (RTIs) has been observed in recent years (2-21). In 2014, a large outbreak of EV-D68 infections occurred in the United States, which raised public health concern owing to severe respiratory illness and neurological complications (22)(23)(24)(25)(26)(27)(28)(29)(30).Although linked to clinical disease, EV-D68 remains poorly characterized. EV-D68 is structurally similar to other enteroviruses (31). The virus possesses a genome approximately 7.4 kb in size, with the capacity to encode a large precursor that is processed into structural proteins (VP1, VP2, VP3, and VP4) and nonstructural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D) (17). Viral infection initiates with sialic acids of the epithelial cells (32). In this process, the virus preferentially binds to ␣2,6-linked sialic acids rather than to ␣2,3-linked sialic acids (33). In addition, EV-D68 is able to infect leukocyte cells (34). As such, active replication of EV-D68 is thought to trigger cytokine responses (35).It is well established that the pattern-recognition receptors (PRRs) initiate innate antiviral immunity through activation of interferon regulatory factor 3 (IRF3), interferon r...

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Enterovirus 68 in Children with Acute Respiratory Tract Infections, Osaka, Japan

Cited by 63 publications

References 12 publications

Molecular Evolution and Intraclade Recombination of Enterovirus D68 during the 2014 Outbreak in the United States

Molecular Evolution and Intraclade Recombination of Enterovirus D68 during the 2014 Outbreak in the United States

Enterovirus 68 in Pediatric Patients Hospitalized for Acute Airway Diseases

3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7

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