Worldwide emergence of multiple clades of enterovirus 68

Tokarz, Rafal; Firth, Cadhla; Madhi, Shabir А.; Howie, Stephen R. C.; Wu, Winfred; Sall, Amadou Alpha; Haq, Saddef; Briese, Thomas; Lipkin, W. Ian

doi:10.1099/vir.0.043935-0

Cited by 196 publications

(293 citation statements)

References 23 publications

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“…EV-D68 was first isolated from children with respiratory infections in California in 1962 (3). It was long considered a rare pathogen, but the frequency of detecting EV-D68 during outbreaks of respiratory disease has increased (4,5) and over the past decades, three clades of EV-D68 (A, B, and C) have emerged and spread worldwide (6,7). EV-D68 infections mostly cause mild respiratory disease but can also result in severe bronchiolitis or pneumonia, especially among children (4,5).…”

mentioning

confidence: 99%

Enterovirus D68 receptor requirements unveiled by haploid genetics

Baggen

Thibaut

Staring

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

118

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Enterovirus D68 (EV-D68) is an emerging pathogen that can cause severe respiratory disease and is associated with cases of paralysis, especially among children. Heretofore, information on host factor requirements for EV-D68 infection is scarce. Haploid genetic screening is a powerful tool to reveal factors involved in the entry of pathogens. We performed a genome-wide haploid screen with the EV-D68 prototype Fermon strain to obtain a comprehensive overview of cellular factors supporting EV-D68 infection. We identified and confirmed several genes involved in sialic acid (Sia) biosynthesis, transport, and conjugation to be essential for infection. Moreover, by using knockout cell lines and gene reconstitution, we showed that both α2,6- and α2,3-linked Sia can be used as functional cellular EV-D68 receptors. Importantly, the screen did not reveal a specific protein receptor, suggesting that EV-D68 can use multiple redundant sialylated receptors. Upon testing recent clinical strains, we identified strains that showed a similar Sia dependency, whereas others could infect cells lacking surface Sia, indicating they can use an alternative, nonsialylated receptor. Nevertheless, these Sia-independent strains were still able to bind Sia on human erythrocytes, raising the possibility that these viruses can use multiple receptors. Sequence comparison of Sia-dependent and Sia-independent EV-D68 strains showed that many changes occurred near the canyon that might allow alternative receptor binding. Collectively, our findings provide insights into the identity of the EV-D68 receptor and suggest the possible existence of Sia-independent viruses, which are essential for understanding tropism and disease.

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mentioning

confidence: 99%

Enterovirus D68 receptor requirements unveiled by haploid genetics

Baggen

Thibaut

Staring

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

118

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“…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%

Antigenic and Receptor Binding Properties of Enterovirus 68

Imamura

Okamoto

Nakakita

et al. 2014

J Virol

114

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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“…The viral genome also revealed 2 deletions at the 5?-UTR spacer region between the end of the internal ribosome entry site and the beginning of the polyprotein open reading frame. These same deletions have been found in EV-D68 isolated in South Africa (29), China (30), and the United States (28). Whether these deletions affect the initiation of translation and virulence will require further investigation.…”

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confidence: 79%

Prevalence and Phylogenetic Characterization of Enterovirus D68 in Pediatric Patients with Acute Respiratory Tract Infection in Thailand

et al. 2016

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SUMMARY: Enterovirus D68 (EV-D68) is associated with severe lower respiratory tract infection and neurological abnormalities including acute myelitis and cranial nerve dysfunction. To determine whether an increased incidence of EV-D68 occurs in Southeast Asia, we retrospectively tested specimens collected from Thai pediatric patients who were less than 5 years of age and presented with acute respiratory tract infections between 2012 and 2014. Reverse transcription-polymerase chain reaction and nucleotide sequencing of the 5 ? -UTR/VP2 region were used to identify EV-D68. We also examined the epidemiological pattern of EV-D68 since 2009, when it was first identified in Thailand, and compiled records of clinical manifestations in children with confirmed EV-D68 infection. From 837 samples, 5 samples (0.6z) tested positive for EV-D68. All patients presented with viral pneumonia and required hospitalization. Phylogenetic analysis of the VP4/VP2 regions revealed that EV-D68 strains circulating in Thailand between 2012 and 2014 were closely related to strains reported in Japan, United Kingdom, China, and France. Continued surveillance of probable EV-D68-associated severe respiratory tract infection and the development of a rapid diagnostic test for EV-D68 are essential in supporting awareness and facilitating disease prevention and control.Enterovirus D68 (EV-D68) is a subtype of Enterovirus enterovirus D within the family Picornaviridae. It was first isolated in the United States in 1962 from respiratory specimens obtained from 4 pediatric patients with pneumonia and bronchiolitis (1). Since then, EV-D68 infections have occurred in small numbers and accounted for only 26 reports among enteroviruses detected in the United States during the 36-year surveillance period from 1970-2005 (2). Between 2008-2010, clusters of EV-D68 emerged in the Philippines, Japan, the Netherlands, and the United States (3). EV-D68 infections have

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Worldwide emergence of multiple clades of enterovirus 68

Cited by 196 publications

References 23 publications

Enterovirus D68 receptor requirements unveiled by haploid genetics

Enterovirus D68 receptor requirements unveiled by haploid genetics

Antigenic and Receptor Binding Properties of Enterovirus 68

Prevalence and Phylogenetic Characterization of Enterovirus D68 in Pediatric Patients with Acute Respiratory Tract Infection in Thailand

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