Emergence of divergent enterovirus (EV) D68 sub-clade D1 strains, northern Italy, September to October 2018

Pellegrinelli, Laura; Giardina, Federica; Lunghi, G.; Renteria, Sara Colonia Uceda; Greco, Letizia; Fratini, Alice; Galli, Cristina; Piralla, Antonio; Binda, Sandro; Pariani, Elena; Baldanti, Fausto

doi:10.2807/1560-7917.es.2018.24.7.1900090

Cited by 31 publications

(47 citation statements)

References 22 publications

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“…The phylogenetic tree showed that most of the Spanish EV-D68 sequences detected during 2016 clustered to the recently described lineage B3 [33], while strains from 2014 and 2015 belonged to subclade B2. Similar results have been obtained with other studies [34,35], suggesting that all the 2016 outbreaks would be [28][29][30]. These findings indicate that although EV-D68 epidemics can be due to the emergence of new lineages, multiple clades have been circulating simultaneously worldwide from 2010 to the present day.…”

Section: Discussionsupporting

confidence: 89%

“…In 2016 and 2018, however, it circulated almost throughout the year, with a higher incidence in spring and summer. This seasonal distribution, in which EV-D68 has periods of low circulation followed by others with high incidence, has been reported in other countries [29,30,[33][34][35], and suggest epidemics of EV-D68 in 2016 and 2018, which was confirmed by phylogenetic analyses of partial VP1 sequences showing increased genetic diversity. The phylogenetic tree showed that most of the Spanish EV-D68 sequences detected during 2016 clustered to the recently described lineage B3 [33], while strains from 2014 and 2015 belonged to subclade B2.…”

Section: Discussionsupporting

confidence: 81%

“…Spanish sequences from 2014 and 2015 clustered in subclade B2 whereas those detected in 2016 belonged to the subclade B3. However, most of the EV-D68 sequences from 2017 and 2018 (35/51, 68.6%) clustered in the recently described subclade D1 [28][29][30]. Finally, strains collected in our laboratory before 2014 (2010-2011) fell into clade A (Figure 3).…”

Section: Ev-d68 Infection In Non-respiratory Diseasesmentioning

confidence: 76%

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Enterovirus D68-associated respiratory and neurological illness in Spain, 2014–2018

González-Sanz

Taravillo

Reina

et al. 2019

Emerging Microbes & Infections

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During 2014, enterovirus D68 (EV-D68) outbreaks were described globally, causing severe respiratory diseases in children and, in some cases, subsequent paralysis. In this study, the type characterization of enterovirus (EV) detected in respiratory illnesses and the epidemiology and clinical association of EV-D68 infections in Spain over a five-year period were described. A total of 546 EV-positive samples from hospitalized patients with respiratory infections were included. EV-D68 was the most frequently detected type (46.6%, 191/410 typed EV). Other EV from species A (25.1%), B (27.8%) and C (0.5%) were also identified. EV-D68 infections were more associated with bronchitis while EV-A/B types were more frequent in upper respiratory illness (p < 0.01). EV-D68 was also detected in patients with neurological symptoms (nine meningitis/meningoencephalitis and eight acute flaccid paralysis cases). Phylogenetic analysis of 3′-VP1 region showed most Spanish EV-D68 sequences from 2014 to 2016 belonged to subclades B2/B3, as other American and European strains circulating during the same period. However, those detected in 2017 and 2018 clustered to the emerged subclade D1. In summary, different EV can cause respiratory infections but EV-D68 was the most prevalent, with several strains circulating in Spain at least since 2014. Association between EV-D68 infection and neurological disease was also described.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 81%

Section: Ev-d68 Infection In Non-respiratory Diseasesmentioning

confidence: 76%

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Enterovirus D68-associated respiratory and neurological illness in Spain, 2014–2018

González-Sanz

Taravillo

Reina

et al. 2019

Emerging Microbes & Infections

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“…Other neurological complications like cranial nerve dysfunction and encephalitis were occasionally reported (11)(12)(13). Since then, biennial epidemics of EV-D68 occur globally, with the largest epidemic in 2018 (14)(15)(16)(17).…”

mentioning

confidence: 99%

Enhanced Enterovirus D68 Replication in Neuroblastoma Cells Is Associated with a Cell Culture-Adaptive Amino Acid Substitution in VP1

Ayudhya

Meijer

Bauer

et al. 2020

mSphere

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Since its emergence in the United States in 2014, enterovirus D68 (EV-D68) has been and is associated with severe respiratory diseases and acute flaccid myelitis. Even though EV-D68 has been shown to replicate in different neuronal cells in vitro, it is currently poorly understood which viral factors contribute to the ability to replicate efficiently in cells of the central nervous system and whether this feature is a clade-specific feature. Here, we determined the replication kinetics of clinical EV-D68 isolates from (sub)clades A, B1, B2, B3, and D1 in human neuroblastoma cells (SK-N-SH). Subsequently, we compared sequences to identify viral factors associated with increased viral replication. All clinical isolates replicated in SK-N-SH cells, although there was a large difference in efficiency. Efficient replication of clinical isolates was associated with an amino acid substitution at position 271 of VP1 (E271K), which was acquired during virus propagation in vitro. Recognition of heparan sulfate in addition to sialic acids was associated with increased attachment, infection, and replication. Removal of heparan sulfate resulted in a decrease in attachment, internalization, and replication of viruses with E271K. Taken together, our study suggests that the replication kinetics of EV-D68 isolates in SK-N-SH cells is not a clade-specific feature. However, recognition of heparan sulfate as an additional receptor had a large effect on phenotypic characteristics in vitro. These observations emphasize the need to compare sequences from virus stocks with clinical isolates in order to retrieve phenotypic characteristics from original virus isolates. IMPORTANCE Enterovirus D68 (EV-D68) causes mild to severe respiratory disease and is associated with acute flaccid myelitis since 2014. Currently, the understanding of the ability of EV-D68 to replicate in the central nervous system (CNS), and whether it is associated with a specific clade of EV-D68 viruses or specific viral factors, is lacking. Comparing different EV-D68 clades did not reveal clade-specific phenotypic characteristics. However, we did show that viruses which acquired a cell culture-adapted amino acid substitution in VP1 (E271K) recognized heparan sulfate as an additional receptor. Recognition of heparan sulfate resulted in an increase in attachment, infection, and replication in neuroblastoma cells compared with viruses without this specific amino acid substitution. The ability of EV-D68 viruses to acquire cell culture-adaptive substitutions which have a large effect in experimental settings emphasizes the need to sequence virus stocks.

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“…Between 1970 and 2005, only 26 cases were reported to the CDC and the virus was generally associated with mild upper respiratory illness [8,9].In 2014, unprecedented outbreaks of EV-D68 associated with severe respiratory disease and acute flaccid myelitis emerged throughout the world [3,. Since 2014, there have been biannual patterns of severe disease associated with EV-D68 [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]. This unique pattern of recurring outbreaks and severe pathology sheds light on the importance of understanding evolutionary changes in contemporary EV-D68 strains.…”

Section: Introductionmentioning

confidence: 99%

Contemporary Enterovirus D68 strains show enhanced replication and translation at 37°C

Smith

Pekosz

2020

Preprint

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Enterovirus D68 (EV-D68) emerged in 2014 as an important pathogen linked to severe lower respiratory disease and acute flaccid myelitis outbreaks. Historically associated with mild common-cold-like symptoms, clusters of severe disease attributed to EV-D68 appeared during a series of outbreaks in 2014, 2016, and 2018. Previous studies of historic EV-D68 strains demonstrated attenuated replication at temperatures of the lower respiratory tract (37°C), when compared to the upper respiratory tract (32°C). By testing a panel of historic and contemporary EV-D68 strains at 32°C and 37°C, we demonstrate that contemporary strains of EV-D68 undergo little to no attenuation at increased temperatures. Contemporary strains produced higher levels of viral proteins at 32°C and 37°C than historic strains, although both strains infected similar numbers of cells and had comparable amounts of replication complexes. IRES activity assays with dual-luciferase reporter plasmids demonstrated enhanced translation in recent EV-D68 strains mapped to regions of variability in the 5' UTR found only in contemporary strains. Using an infectious clone system, we demonstrate that the translation advantage dictated by the 5' UTR does not solely mediate temperature sensitivity. The strain-dependent effects of temperature on the EV-D68 life cycle gives insight into the susceptibility of the lower respiratory system to contemporary strains. IMPORTANCEEnterovirus-D68 (EV-D68) emerged in 2014 as a causative agent of biannual severe pediatric respiratory disease and acute flaccid myelitis (AFM). We show that recent EV-D68 viruses have gained the ability to replicate at 37⁰C. Enhanced virus protein translation seemed to correlate with enhanced virus replication at 37⁰C but other genetic factors are also contributing to this phenotype. An enhanced ability to replicate at core body temperature may have allowed EV-D68 to penetrate both lower in the respiratory tract and into the central nervous system, explaining the recent surge in severe disease associated with virus infection.

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Emergence of divergent enterovirus (EV) D68 sub-clade D1 strains, northern Italy, September to October 2018

Cited by 31 publications

References 22 publications

Enterovirus D68-associated respiratory and neurological illness in Spain, 2014–2018

Enterovirus D68-associated respiratory and neurological illness in Spain, 2014–2018

Enhanced Enterovirus D68 Replication in Neuroblastoma Cells Is Associated with a Cell Culture-Adaptive Amino Acid Substitution in VP1

Contemporary Enterovirus D68 strains show enhanced replication and translation at 37°C

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