Calcium signals and calpain-dependent necrosis are essential for release of coxsackievirus B from polarized intestinal epithelial cells

Bozym, Rebecca A.; Patel, Khushbu; White, Carl; Cheung, King‐Ho; Bergelson, Jeffrey M.; Morosky, Stefanie; Coyne, Carolyn B.

doi:10.1091/mbc.e11-02-0094

Cited by 40 publications

(56 citation statements)

References 47 publications

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“…(Fig. 2C, Left), and the mislocalization of the tight junction protein occludin, which we have shown previously is disrupted by enterovirus infection (24) (Fig. 2C, Right).…”

Section: Resultssupporting

confidence: 67%

See 1 more Smart Citation

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner

Drummond

Bolock

et al. 2017

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

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127

173

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Enteroviruses are among the most common viral infectious agents of humans and are primarily transmitted by the fecal-oral route. However, the events associated with enterovirus infections of the human gastrointestinal tract remain largely unknown. Here, we used stem cell-derived enteroids from human small intestines to study enterovirus infections of the intestinal epithelium. We found that enteroids were susceptible to infection by diverse enteroviruses, including echovirus 11 (E11), coxsackievirus B (CVB), and enterovirus 71 (EV71), and that contrary to an immortalized intestinal cell line, enteroids induced antiviral and inflammatory signaling pathways in response to infection in a virus-specific manner. Furthermore, using the Notch inhibitor dibenzazepine (DBZ) to drive cellular differentiation into secretory cell lineages, we show that although goblet cells resist E11 infection, enteroendocrine cells are permissive, suggesting that enteroviruses infect specific cell populations in the human intestine. Taken together, our studies provide insights into enterovirus infections of the human intestine, which could lead to the identification of novel therapeutic targets and/or strategies to prevent or treat infections by these highly clinically relevant viruses.E nteroviruses are significant sources of human infections worldwide and are primarily transmitted by the fecal-oral route. Nonpoliovirus enteroviruses include coxsackievirus, echovirus, enterovirus 71 (EV71), and enterovirus D68 (EV-D68) and are small (∼30 nm) single-stranded RNA viruses belonging to the Picornaviridae family. In many cases, enterovirus infections remain asymptomatic, whereas in others, infection is associated with mild flu-like symptoms or much more severe outcomes such as type I diabetes, encephalomyelitis, encephalitis, myocarditis, dilated cardiomyopathy, pleurodynia, acute flaccid paralysis, or even death.The human gastrointestinal (GI) tract is a complex organ, with an epithelial surface that must provide a protective and immunological barrier in a complex and diverse microbial environment. The epithelium of the small intestine contains at least seven distinct cell subtypes that are responsible for the physiological functions of the intestine, which include nutrient absorption and defense against pathogens. The lack of models that recapitulate the complexity of the GI tract has hindered studies into many aspects of enterovirus infection in this specialized environment. Although murine models have been developed for the study of enterovirusinduced disease (1-4), many of these models require intraperitoneal (i.p.) infection, thereby bypassing the GI tract, or require ablation of the host innate immune system (5, 6). Coupled with species differences between humans and mice, there remains a need to develop human-based platforms to model enterovirus infections of the GI tract.The full repertoire of mature cells in the small intestine in vivo includes those of absorptive (enterocytes) and secretory (Paneth, goblet, and enteroendocrine) lin...

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“…(Fig. 2C, Left), and the mislocalization of the tight junction protein occludin, which we have shown previously is disrupted by enterovirus infection (24) (Fig. 2C, Right).…”

Section: Resultssupporting

confidence: 67%

“…1 B and C). To profile the transcriptional differences between human enteroids and Caco-2 cells, an immortalized colorectal cell line commonly used in enterovirus research (18,(23)(24)(25)(26), we used RNA-seq. Not surprisingly, the transcriptional profiles of primary enteroids were distinct from Caco-2 cells and clustered accordingly (Fig.…”

Section: Resultsmentioning

confidence: 99%

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner

Drummond

Bolock

et al. 2017

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

Self Cite

127

173

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“…Internalization of coxsackievirus-B also requires the TJ protein occludin (Coyne et al 2007). The subsequent release from epithelial cells has been suggested to occur through a calcium signal and calpain-dependent necrosis of the infected cells (Bozym et al 2011). …”

Section: Translocation Across Enterocytesmentioning

confidence: 99%

Concepts and Mechanisms: Crossing Host Barriers

Doran

Banerjee

Disson

et al. 2013

Cold Spring Harbor Perspectives in Medicine

110

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“…Another is that in many of the cell types studied in vitro , the main cell death pathway induced upon EV infection is apoptosis and necrosis seems to be uninvolved, or not involved to any significant degree ( Section 3.1 ). However, we recently showed that a polarized intestinal epithelial cell line undergoes Ca2+-dependent necrotic cell death upon CVB3 infection (102). As described above for PV-infection in neurons (65), cell death induction was dependent on Ca 2+ release from the ER upon CVB3 infection (102).…”

Section: Induction Of Cell Death Upon Enterovirus Infectionmentioning

confidence: 99%

“…However, we recently showed that a polarized intestinal epithelial cell line undergoes Ca2+-dependent necrotic cell death upon CVB3 infection (102). As described above for PV-infection in neurons (65), cell death induction was dependent on Ca 2+ release from the ER upon CVB3 infection (102). However, whereas this Ca 2+ release in PV-infected neurons leads to apoptotic cell death, it induces calpain-mediated necrotic cell death in intestinal epithelial cells infected with CVB3 (65,102).…”

Section: Induction Of Cell Death Upon Enterovirus Infectionmentioning

confidence: 99%

Death waits for no man – Does it wait for a virus? How enteroviruses induce and control cell death

Harris

Coyne

2014

Cytokine & Growth Factor Reviews

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Enteroviruses (EVs) are the most common human viral pathogens. They cause a variety of pathologies, including myocarditis and meningoencephalopathies, and have been linked to the onset of type I diabetes. These pathologies result from the death of cells in the myocardium, central nervous system, and pancreas, respectively. Understanding the role of EVs in inducing cell death is crucial to understanding the etiologies of these diverse pathologies. EVs both induce and delay host cell death, and their exquisite control of this balance is crucial for their success as human viral pathogens. Thus, EVs are tightly involved with cell death signaling pathways and interact with host cell signaling at multiple points Here, we review the literature detailing the mechanisms of EV-induced cell death. We discuss the mechanisms by which EVs induce cell death, the signaling pathways involved in these pathways, and the strategies by which EVs antagonize cell death pathways. We also discuss the role of cell death in both the resulting pathology in the host and in the facilitation of viral spread.

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Calcium signals and calpain-dependent necrosis are essential for release of coxsackievirus B from polarized intestinal epithelial cells

Cited by 40 publications

References 47 publications

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner

Enteroviruses infect human enteroids and induce antiviral signaling in a cell lineage-specific manner

Concepts and Mechanisms: Crossing Host Barriers

Death waits for no man – Does it wait for a virus? How enteroviruses induce and control cell death

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