Upsurge of human enterovirus 68 infections in patients with severe respiratory tract infections

Rahamat‐Langendoen, Janette; Riezebos‐Brilman, Annelies; Borger, Renze; Heide, Reina van der; Brandenburg, A. H.; Schölvinck, Elisabeth H.; Niesters, Hubert G. M.

doi:10.1016/j.jcv.2011.06.019

Cited by 97 publications

(121 citation statements)

References 12 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…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)(5)(6)(7)(8)(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).…”

mentioning

confidence: 99%

“…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)(5)(6)(7)(8)(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)(5)(6)(7)(8).…”

mentioning

confidence: 99%

“…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)(5)(6)(7)(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).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Enterovirus 68 in Pediatric Patients Hospitalized for Acute Airway Diseases

Renois¹,

Bouin²,

Andréoletti³

2013

J Clin Microbiol

View full text Add to dashboard Cite

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...

show abstract

“…Cases were defined as persons ≤18 years of age who were hospitalized and tested positive for EV-D68 infection by polymerase chain reaction (PCR) testing and/or genetic sequencing of the virus using standard enterovirus genotyping methods (19,20), or an EV-D68 specific real-time PCR (21), from any clinical specimen collected in September 2014.…”

Section: Case Definitionmentioning

confidence: 99%

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

et al. 2015

CCDR

View full text Add to dashboard Cite

show abstract

Upsurge of human enterovirus 68 infections in patients with severe respiratory tract infections

Cited by 97 publications

References 12 publications

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

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

Enterovirus 68 in Pediatric Patients Hospitalized for Acute Airway Diseases

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

Contact Info

Product

Resources

About