Outbreak of Life‐Threatening Coxsackievirus B1 Myocarditis in Neonates

Verma, Natasha; Zheng, Xiaotian; Harris, Michelle U.; Cadichon, Sandra B.; Melín-Aldana, Héctor; Khetsuriani, Nino; Oberste, M. Steven; Shulman, Stanford T.

doi:10.1086/605089

Cited by 67 publications

(40 citation statements)

References 16 publications

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“…Enteroviruses have evolved mechanisms to subvert the placental protective barrier, as incidences of fetal disease and death have been reported (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Here we utilized the BeWo trophoblast cell line as a model of placental trophoblasts to delineate the key cellular components that facilitate CVB entry into the trophoblast monolayer.…”

Section: Discussionmentioning

confidence: 99%

“…Maternal CVB infection and consequential fetal transmission have been associated with severe pathological outcomes, including congenital skin lesions (15), the development of type I diabetes (16,17) and thyroiditis (18) later in life, hydrops fetalis (19), fetal myocarditis (20)(21)(22), meningoencephalitis (23), neurodevelopmental delays (24), fetal sepsis (25), miscarriage (26), and stillbirth (27,28). Currently, testing for enterovirus infections during pregnancy is not routine, and thus there is a lack of data regarding their prevalence.…”

mentioning

confidence: 99%

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Lipid Raft- and Src Family Kinase-Dependent Entry of Coxsackievirus B into Human Placental Trophoblasts

Delorme-Axford

Sadovsky

Coyne

2013

J Virol

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bMaternal-fetal transmission of group B coxsackieviruses (CVB) during pregnancy has been associated with a number of diverse pathological outcomes, including hydrops fetalis, fetal myocarditis, meningoencephalitis, neurodevelopmental delays, congenital skin lesions, miscarriage, and/or stillbirth. Throughout pregnancy, the placenta forms a critical antimicrobial protective barrier at the maternal-fetal interface. Despite the severity of diseases accompanying fetal CVB infections, little is known regarding the strategies used by CVB to gain entry into placental trophoblasts. Here we used both a trophoblast cell line and primary human trophoblasts to demonstrate the mechanism by which CVB gains entry into polarized placental trophoblasts. Our studies revealed that the kinetics of CVB entry into placental trophoblasts are similar to those previously described for polarized intestinal epithelial cells. Likewise, CVB entry into placental trophoblasts requires decay-accelerating factor (DAF) binding and involves relocalization of the virus from the apical surface to intercellular tight junctions. In contrast, we have identified a divergent mechanism for CVB entry into polarized trophoblasts that is clathrin, caveolin-1, and dynamin II independent but requires intact lipid rafts. In addition, we found that members of the Src family of tyrosine kinases were required for CVB entry. Our studies highlight the complexity of viral entry into human placental trophoblasts and may serve as a model for mechanisms used by diverse pathogens to penetrate the placental barrier.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Lipid Raft- and Src Family Kinase-Dependent Entry of Coxsackievirus B into Human Placental Trophoblasts

Delorme-Axford

Sadovsky

Coyne

2013

J Virol

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“…Enteroviruses also represent a perennially epidemic public health threat due to their genetic diversity and to the regular emergence of new, more pathogenic variants of known serotypes. For example, a new variant of coxsackievirus B1 (CVB1) emerged in the United States in 2007 and was associated with reports of sepsis and myocarditis in newborns at more than 40 locations in the continental United States and Alaska (5,6). Similarly, in 2014, an outbreak of enterovirus D68 (EV-D68), previously likened to rhinoviruses in pathogenicity (7), was responsible for more than 1,100 reports of severe respiratory disease and was linked to more than 100 cases of acute flaccid myelitis (8)(9)(10)(11)(12).…”

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confidence: 99%

Discovery of Structurally Diverse Small-Molecule Compounds with Broad Antiviral Activity against Enteroviruses

Zuo

Kye

Quinn

et al. 2016

Antimicrob Agents Chemother

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Antiviral drugs do not currently exist for the treatment of enterovirus infections, which are often severe and potentially lifethreatening. We conducted high-throughput molecular screening and identified a structurally diverse set of compounds that inhibit the replication of coxsackievirus B3, a commonly encountered enterovirus. These compounds did not interfere with the function of the viral internal ribosome entry site or with the activity of the viral proteases, but they did drastically reduce the synthesis of viral RNA and viral proteins in infected cells. Sequence analysis of compound-resistant mutants suggests that the viral 2C protein is targeted by most of these compounds. These compounds demonstrated antiviral activity against a panel of the most commonly encountered enteroviruses and thus represent potential leads for the development of broad-spectrum anti-enteroviral drugs.

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“…CVB1 was initially isolated in 1948 near Coxsackie, NY, but a new variant of CVB1 emerged in 2007 and was detected at nearly 50 sites in the United States. Large clusters of cases occurred in Chicago, IL, and Los Angeles, CA, including cases of sepsis, myocarditis, and deaths among newborns (6,42,45). Since then, CVB1 has been the most commonly identified enterovirus in the United States (7).…”

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confidence: 99%

Fluoxetine Is a Potent Inhibitor of Coxsackievirus Replication

Zuo

Quinn²,

Kye³

et al. 2012

Antimicrob Agents Chemother

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ABSTRACTNo antiviral drugs currently exist for the treatment of enterovirus infections, which are often severe and potentially life threatening. Molecular screening of small molecule libraries identified fluoxetine, a selective serotonin reuptake inhibitor, as a potent inhibitor of coxsackievirus replication. Fluoxetine did not interfere with either viral entry or translation of the viral genome. Instead, fluoxetine and its metabolite norfluoxetine markedly reduced the synthesis of viral RNA and protein. In view of its favorable pharmacokinetics and safety profile, fluoxetine warrants additional study as a potential antiviral agent for enterovirus infections.

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Outbreak of Life‐Threatening Coxsackievirus B1 Myocarditis in Neonates

Cited by 67 publications

References 16 publications

Lipid Raft- and Src Family Kinase-Dependent Entry of Coxsackievirus B into Human Placental Trophoblasts

Lipid Raft- and Src Family Kinase-Dependent Entry of Coxsackievirus B into Human Placental Trophoblasts

Discovery of Structurally Diverse Small-Molecule Compounds with Broad Antiviral Activity against Enteroviruses

Fluoxetine Is a Potent Inhibitor of Coxsackievirus Replication

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