Exosomes Facilitate Transmission of Enterovirus A71 From Human Intestinal Epithelial Cells

Huang, Hsing‐I; Lin, Jhao-Yin; Chiang, Hsiao-Chu; Huang, Pen-Nien; Lin, Qing-Dong; Shih, Shin‐Ru

doi:10.1093/infdis/jiaa174

Cited by 29 publications

(26 citation statements)

References 45 publications

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“…Moreover, these cells have a more homogeneous brush border expression and contain more microvillar proteins than the parental Caco-2 cells [ 30 ]. C2BBe1 cells can be further differentiated by the growth of the trans-well filters inducing structure of the microvilli ( Figure 3 A) [ 27 , 30 ]. Thus, we examined whether cellular differentiation can regulate the expression of these two receptors (ACE2 and TMPRSS2).…”

Section: Resultsmentioning

confidence: 99%

“…Differentiation of C2BBe1 was performed as previously described by Huang et al [ 27 ]. Briefly, the C2BBe1 cells were seeded on trans-well inserts (0.4 µm pore size, 12-mm membrane diameter; Corning, Kennebunk, ME, USA) at a density of 5 × 10 5 cells/cm 2 and cultured in 1:1 ratio of MEM/EBSS containing 10% FBS: enterocyte differentiation medium (Corning, Kennebunk, ME, USA).…”

Section: Methodsmentioning

confidence: 99%

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Robust and persistent SARS-CoV-2 infection in the human intestinal brush border expressing cells

Lee

Yoon

Myoung

et al. 2020

Emerging Microbes & Infections

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Studies on patients with the coronavirus disease-2019 (COVID-19) have implicated that the gastrointestinal (GI) tract is a major site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We established a human GI tract cell line model highly permissive to SARS-CoV-2. These cells, C2BBe1 intestinal cells with a brush border having high levels of transmembrane serine protease 2 (TMPRSS2), showed robust viral propagation, and could be persistently infected with SARS-CoV-2, supporting the clinical observations of persistent GI infection in COVID-19 patients. Ectopic expression of viral receptors revealed that the levels of angiotensin-converting enzyme 2 (ACE2) expression confer permissiveness to SARS-CoV-2 infection, and TMPRSS2 greatly facilitates ACE2-mediated SARS-CoV-2 dissemination. Interestingly, ACE2 but not TMPRSS2 expression was significantly promoted by enterocytic differentiation, suggesting that the state of enterocytic differentiation may serve as a determining factor for viral propagation. Thus, our study sheds light on the pathogenesis of SARS-CoV-2 in the GI tract.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Robust and persistent SARS-CoV-2 infection in the human intestinal brush border expressing cells

Lee

Yoon

Myoung

et al. 2020

Emerging Microbes & Infections

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“…Most of the human-pathogenic enteroviruses belong to the species Enterovirus A to D or Rhinovirus A to C. Humans mainly acquire enteroviruses through the fecal-oral route and, sometimes, via the respiratory tract. After ingestion, enteroviruses replicate in the pharynx and small intestinal submucosal lymphoid tissues and mature polarized enterocytes [ 2 ]. Then, enteroviruses pass to regional lymph nodes and cause transient viremia to infect reticuloendothelial tissues including liver, spleen, and bone marrow.…”

Section: Introductionmentioning

confidence: 99%

Development of Three-Dimensional Human Intestinal Organoids as a Physiologically Relevant Model for Characterizing the Viral Replication Kinetics and Antiviral Susceptibility of Enteroviruses

et al. 2021

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Enteroviruses are important causes of hand, foot, and mouth disease, respiratory infections, and neurological infections in human. A major hurdle for the development of anti-enterovirus agents is the lack of physiologically relevant evaluation platforms that closely correlate with the in vivo state. We established the human small intestinal organoids as a novel platform for characterizing the viral replication kinetics and evaluating candidate antivirals for enteroviruses. The organoids supported productive replication of enterovirus (EV)-A71, coxsackievirus B2, and poliovirus type 3, as evidenced by increasing viral loads, infectious virus titers, and the presence of cytopathic effects. In contrast, EV-D68, which mainly causes respiratory tract infection in humans, did not replicate significantly in the organoids. The differential expression profiles of the receptors for these enteroviruses correlated with their replication kinetics. Using itraconazole as control, we showed that the results of various antiviral assays, including viral load reduction, plaque reduction, and cytopathic effect inhibition assays, were highly reproducible in the organoids. Moreover, itraconazole attenuated virus-induced inflammatory response in the organoids, which helped to explain its antiviral effects and mechanism. Collectively, these data showed that the human small intestinal organoids may serve as a robust platform for investigating the pathogenesis and evaluating antivirals for enteroviruses.

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“…The inhibition of caspase 3 inhibits EV-A71 replication in rhabdomyosarcoma (RD) cells 31 . In our previous report, treatment with the caspase 3 inhibitor Z-VAD decreased EV-A71 replication in RD cells 32 . However, treatment with the caspase 3 inhibitor Z-VAD did not inhibit viral growth in differentiated IMR-32 cells (Figure S2 ).…”

Section: Resultsmentioning

confidence: 77%

“…The inhibition of caspase 3 inhibits EV-A71 replication in rhabdomyosarcoma (RD) cells 31 . In our previous report, treatment with the caspase 3 inhibitor Z-VAD decreased EV-A71 replication in RD cells 32 . However, treatment with the caspase www.nature.com/scientificreports/ www.nature.com/scientificreports/ (PE) to form LC3-II, so the level of LC3-II correlates with the number of autophagosomes 34 .…”

Section: Caspase 3 Caspase 8 and Caspase 9 Are Not Activated In Ev-amentioning

confidence: 77%

Autophagy is induced and supports virus replication in Enterovirus A71-infected human primary neuronal cells

Lin

Huang

2020

Sci Rep

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Enterovirus A71 (EV-A71), which belongs to the family Picornaviridae, can invade the central nervous system (CNS) and cause severe CNS complications or death. The EV-A71 antigen has been detected in the neurons in the brains of humans who died from EV-A71 infection. However, the effect of EV-A71 infection on human neuronal cells remains poorly understood. Human neural stem cells (NSCs) and IMR-32 neuroblastoma cells were differentiated into neuronal cells for this study. Although the neuronal cells were permissive to EV-A71 infection, EV-A71 infection did not induce an obvious cytopathic effect on the neuronal cells. EV-A71 infection did not induce apoptosis in neuronal cells. However, autophagy and autophagic flux were induced in EV-A71-infected neuronal cells. The production of autophagosomes was shown to be important for EV-A71 viral RNA (vRNA) replication in neuronal cells.

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Exosomes Facilitate Transmission of Enterovirus A71 From Human Intestinal Epithelial Cells

Cited by 29 publications

References 45 publications

Robust and persistent SARS-CoV-2 infection in the human intestinal brush border expressing cells

Robust and persistent SARS-CoV-2 infection in the human intestinal brush border expressing cells

Development of Three-Dimensional Human Intestinal Organoids as a Physiologically Relevant Model for Characterizing the Viral Replication Kinetics and Antiviral Susceptibility of Enteroviruses

Autophagy is induced and supports virus replication in Enterovirus A71-infected human primary neuronal cells

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