Enterovirus 68 among Children with Severe Acute Respiratory Infection, the Philippines

Imamura, Tadatsugu; Fuji, Naoko; Suzuki, Akira; Tamaki, Raita; Saito, Mariko; Aniceto, Rapunzel; Galang, Hazel; Sombrero, Lydia; Lupisan, Soccoro; Oshitani, Hitoshi

doi:10.3201/eid1708.101328

Cited by 95 publications

(133 citation statements)

References 23 publications

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“…According to our previous reports, most of the EV68 strains detected in the Philippines belonged to lineage 2, and a few of them belonged to lineage 3 (4,10). The VP1 sequences detected in the Philippines and other countries demonstrated that the amino acid sequence patterns in BC and DE loops were correlated with the categorization of EV68 into the 3 lineages (6,8,10).…”

Section: H Uman Enterovirus 68 (Ev68) (Species Human Enterovirus D;mentioning

confidence: 99%

“…In an enterovirus surveillance conducted in the United States from 1970 to 2005, only a total of 26 strains were reported over 35 years (2). However, the number of reported EV68 cases increased dramatically in the late 2000s, in different parts of the world (3)(4)(5)(6)(7)(8). The underlying molecular mechanism for this sudden increase of EV68 detections in recent years is still unknown.…”

Section: H Uman Enterovirus 68 (Ev68) (Species Human Enterovirus D;mentioning

confidence: 99%

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Antigenic and Receptor Binding Properties of Enterovirus 68

Imamura

Okamoto

Nakakita

et al. 2014

J Virol

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113

127

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Increased detection of enterovirus 68 (EV68) among patients with acute respiratory infections has been reported from different parts of the world in the late 2000s since its first detection in pediatric patients with lower-respiratory-tract infections in 1962. However, the underlying molecular mechanisms for this trend are still unknown. We therefore aimed to study the antigenicity and receptor binding properties of EV68 detected in recent years in comparison to the prototype strain of EV68, the Fermon strain. We first performed neutralization (NT) and hemagglutination inhibition (HI) tests using antisera generated for EV68 strains detected in recent years. We found that the Fermon strain had lower HI and NT titers than recently detected EV68 strains. The HI and NT titers were also significantly different between strains of different genetic lineages among recently detected EV68 strains. We further studied receptor binding specificities of EV68 strains for sialyloligosaccharides using glycan array analysis. In glycan array analysis, all tested EV68 strains showed affinity for ␣2-6-linked sialic acids (␣2-6 SAs) compared to ␣2-3 SAs. Our study demonstrates that emergence of strains with different antigenicity is the possible reason for the increased detection of EV68 in recent years. Additionally, we found that EV68 preferably binds to ␣2-6 SAs, which suggests that EV68 might have affinity for the upper respiratory tract. IMPORTANCE Numbers of cases of enterovirus 68 (EV68) infection in different parts of the world increased significantly in the late 2000s.We studied the antigenicity and receptor binding properties of recently detected EV68 strains in comparison to the prototype strain of EV68, Fermon. The hemagglutination inhibition (HI) and neutralization (NT) titers were significantly different between strains of different genetic lineages among recently detected EV68 strains. We further studied receptor binding specificities of EV68 strains for sialyloligosaccharides using glycan array analysis, which showed affinity for ␣2-6-linked sialic acids (␣2-6 SAs) compared to ␣2-3 SAs. Our study suggested that the emergence of strains with different antigenicities was the possible reason for the increased detections of EV68 in recent years. Additionally, we revealed that EV68 preferably binds to ␣2-6 SAs. This is the first report describing the properties of EV68 receptor binding to the specific types of sialic acids.

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Section: H Uman Enterovirus 68 (Ev68) (Species Human Enterovirus D;mentioning

confidence: 99%

Section: H Uman Enterovirus 68 (Ev68) (Species Human Enterovirus D;mentioning

confidence: 99%

Antigenic and Receptor Binding Properties of Enterovirus 68

Imamura

Okamoto

Nakakita

et al. 2014

J Virol

Self Cite

113

127

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“…It was first detected in 1962 in California, 2 and has since been detected in several countries, including the Philippines, Japan and the Netherlands, as well as in previous clusters in the United States. [3][4][5] However, by the end of 2014, a total of more than 1000 cases from 49 states in the US were reported. 6 Almost 40% of samples submitted to the Centers for Disease Control and Prevention (CDC) for suspected EV-D68 were positive for EV-D68, 6 and the genotype spread further north into Canada.…”

mentioning

confidence: 99%

Clinical severity of pediatric respiratory illness with enterovirus D68 compared with rhinovirus or other enterovirus genotypes

Mertz

Alawfi

Pernica

et al. 2015

CMAJ

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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).…”

mentioning

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 among Children with Severe Acute Respiratory Infection, the Philippines

Abstract: TOC summary: Enterovirus 68 was found in 21 children with severe pneumonia.

Cited by 95 publications

References 23 publications

Antigenic and Receptor Binding Properties of Enterovirus 68

Antigenic and Receptor Binding Properties of Enterovirus 68

Clinical severity of pediatric respiratory illness with enterovirus D68 compared with rhinovirus or other enterovirus genotypes

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

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