Enterovirus 68 infection in children with asthma attacks: virus-induced asthma in Japanese children

Hasegawa, Shunji; Hirano, Reiji; Okamoto-Nakagawa, Reiko; Ichiyama, Takashi; Shirabe, Komei

doi:10.1111/j.1398-9995.2011.02725.x

Cited by 64 publications

(64 citation statements)

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“…A total of 62 EV-D68-positive samples were chosen for complete genome sequencing, including 60 clinical samples from the 2014 outbreak collected from Children's Mercy Hospital, Kansas City, MO; one preoutbreak sample from Vanderbilt University Medical Center, Nashville, TN, collected in 2012; and one sample from the American Type Culture Collection (ATCC), VR-1197. Oligo(dT) 20 and/or two primers specific to the 3=-terminal region of the virus were used for reverse transcription ( Table 1). The general pattern of primer sites and the locations of primer targets in EV-D68 genomes are shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…(i) Full-length genome amplicons containing the 3= poly(A) tail (FL-A) were generated from the cDNA generated by oligo(dT) 20 using D68_1F and M13-dt18 (reverse primer). (ii) Fulllength genome amplification excluding the 3= poly(A) tail (FL) was performed using gene-specific RT mix primers and PCR primer D68_1F and a 1:1 mix of D68_7333AR and D68_7333BR.…”

Section: Rna Extraction and Reverse Transcription-pcr (Rt-pcr)mentioning

confidence: 99%

“…Lysate was transferred to a ZR96 spin plate (Zymo), and samples were processed according to the manufacturer's protocol. The cDNA was generated using SuperScript III reverse transcriptase (Thermo Fisher Scientific, MA) from 4 l undiluted RNA and either oligo(dT) 20 or a 1:1 mix of two primers specific to the 3=-terminal region (D68_7333AR and D68_7333BR) ( Table 1).…”

Section: Rna Extraction and Reverse Transcription-pcr (Rt-pcr)mentioning

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: Resultsmentioning

confidence: 99%

Section: Rna Extraction and Reverse Transcription-pcr (Rt-pcr)mentioning

confidence: 99%

Section: Rna Extraction and Reverse Transcription-pcr (Rt-pcr)mentioning

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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“…Asthma or wheezing appears to be a risk factor for severe disease (30,47). Although the underlying events are largely 1, 3, 5, and 7) or GFP-3C (lanes 2, 4, 6, and 8), as indicated.…”

Section: Discussionmentioning

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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“…Infections were reported in both children and adults; however, children aged less than 1 month to 4 years old were most commonly affected. Children with underlying respiratory disease (e.g., asthma, wheezing, and bronchiolitis) and immunocompromised adults have been reported to experience more severe disease (13,14). The epidemiology and full spectrum of disease caused by EV-D68 remains unclear (12,13), primarily due to its infrequent detection.…”

Section: Introductionmentioning

confidence: 99%

Surveillance summary of hospitalized pediatric enterovirus D68 cases in Canada, September 2014

et al. 2015

CCDR

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Enterovirus 68 infection in children with asthma attacks: virus-induced asthma in Japanese children

Cited by 64 publications

References 5 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

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

Surveillance summary of hospitalized pediatric enterovirus D68 cases in Canada, September 2014

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