Enterovirus D68–Associated Acute Respiratory Distress Syndrome in Adult, United States, 2014

Farrell, John; Ikladios, Ossama; Wylie, Kristine M.; O׳Rourke, Lindsay M.; Lowery, Kristin S.; Cromwell, Jenna; Wylie, Todd; Melendez, Elsa L. Vazquez; Makhoul, Yves; Sampath, Rangarajan; Bonomo, Robert A.; Storch, Gregory A.

doi:10.3201/eid2105.142033

Cited by 23 publications

(18 citation statements)

References 8 publications

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“…Blood samples were collected before and after viral infection. Animal feces, nasal washes, and throat swabs were collected on days 1,3,5,7,9,11,13, and 15 after the challenge and frozen (−80 • C) until analysis. After infection, on days 3, 5, 7, 9, the ferrets were euthanized with an intramuscular injection of a ketamine (20 mg/kg), then the organs or tissues were harvested for histopathology and viral distribution analysis.…”

Section: Ethics Statement and Animal Experimentsmentioning

confidence: 99%

“…Viral load in feces (A) and nasal washes (B) and throat swabs (C) of infected ferrets were detected in the whole course of EV-D68 infection(1,3,5,7,9,11,13,15 days post-infection); (D) Viral RNA was picked up from blood samples and analyzed by Taqman real-time quantitative PCR assay, according to the protocols provided by the qPCR kit. Each blood samples were gathered during the whole EV-D68 infection course(1,3,5,7,9,11,13,15 days post-infection); (E)Viral load in lung of ferret at different day post-infection (3, 5, 7, 9 days post-infection); (F) Viral load in lymph nodes at different day post-infection(3, 5, 7, 9 days post-infection). The vitro-synthesized RNA was applied to quantify the viral copies of each RNA sample, and viral RNA's relative copies for each sample was calculated by the mathematical formula as follow: [(µg of RNA/µL)/(molecular weight)] × Avogadro's number = viral copy number/µL.…”

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confidence: 99%

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Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo)

Zheng

Sun

Guo

et al. 2017

Viruses

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Data from EV-D68-infected patients demonstrate that pathological changes in the lower respiratory tract are principally characterized by severe respiratory illness in children and acute flaccid myelitis. However, lack of a suitable animal model for EV-D68 infection has limited the study on the pathogenesis of this critical pathogen, and the development of a vaccine. Ferrets have been widely used to evaluate respiratory virus infections. In the current study, we used EV-D68-infected ferrets as a potential animal to identify impersonal indices, involving clinical features and histopathological changes in the upper and lower respiratory tract (URT and LRT). The research results demonstrate that the EV-D68 virus leads to minimal clinical symptoms in ferrets. According to the viral load detection in the feces, nasal, and respiratory tracts, the infection and shedding of EV-D68 in the ferret model was confirmed, and these results were supported by the EV-D68 VP1 immunofluorescence confocal imaging with α2,6-linked sialic acid (SA) in lung tissues. Furthermore, we detected the inflammatory cytokine/chemokine expression level, which implied high expression levels of interleukin (IL)-1a, IL-8, IL-5, IL-12, IL-13, and IL-17a in the lungs. These data indicate that systemic observation of responses following infection with EV-D68 in ferrets could be used as a model for EV-D68 infection and pathogenesis.

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Section: Ethics Statement and Animal Experimentsmentioning

confidence: 99%

mentioning

confidence: 99%

Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo)

Zheng

Sun

Guo

et al. 2017

Viruses

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“…A global upsurge of EV-D68 infections in patients with respiratory tract infections (RTIs) has been observed in recent years (2-21). 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).…”

Section: Ev-d68 Is a Globally Emerging Pathogen But The Molecular Bamentioning

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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“…It was first isolated from samples obtained in California in 1962 from four children with pneumonia and bronchiolitis (Schieble, Fox, & Lennette, ). During the past 10 years, EVD68 infection outbreaks have been reported in Italy, the United States, Germany, China, and several other countries (Esposito et al, ; Farrell et al, ; Reiche et al, ; Zhang et al, ), with a record number of confirmed cases in 2014 (http://www.cdc.gov/non-polio-enterovirus/about/ev-d68.html). Unfortunately, no vaccines for prevention or medications for treatment are currently available.…”

Section: Introductionmentioning

confidence: 99%

Effect of ingredients from Chinese herbs on enterovirus D68 production

Meng

Liu

et al. 2018

Phytotherapy Research

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Human enterovirus 68 (EVD68) is a primary causative agent for respiratory illness worldwide. Until now, there has been no available medication for treating EVD68related diseases. Rheum emodin, artemisinin, astragaloside, pseudolaric acid B, oridonin, and erianin are natural extracts from Chinese herbs that have traditionally been used for the treatment and prevention of epidemic diseases. Our results showed that pseudolaric acid B protected cells from EVD68-induced cytopathic effects and decreased viral production. However, the same effects were not observed with rheum emodin, astragaloside, or artemisinin. Pseudolaric acid B inhibited EVD68 production by manipulating the host cell cycle in G2/M phase. Further, either oridonin or erianin related G2/M arrest also inhibited viral production. Due to inducing G2/M phase arrest, pseudolaric acid B, oridonin, and erianin might be good candidates for inhibiting EVD68 production, and Chinese herbs with natural compounds inducing G2/M arrest should be considered for the treatment of EVD68-related diseases. KEYWORDS enterovirus D68 (EVD68), G2/M arrest, natural compounds, viral production

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Enterovirus D68–Associated Acute Respiratory Distress Syndrome in Adult, United States, 2014

Cited by 23 publications

References 8 publications

Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo)

Nasal Infection of Enterovirus D68 Leading to Lower Respiratory Tract Pathogenesis in Ferrets (Mustela putorius furo)

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

Effect of ingredients from Chinese herbs on enterovirus D68 production

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