Coxsackievirus Entry across Epithelial Tight Junctions Requires Occludin and the Small GTPases Rab34 and Rab5

Coyne, Carolyn B.; Shen, Le; Turner, Jerrold R.; Bergelson, Jeffrey M.

doi:10.1016/j.chom.2007.07.003

Cited by 211 publications

(211 citation statements)

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“…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.

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127

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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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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.

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127

173

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“…More recently, it has been recognized that occludin endocytosis is a common feature of responses not only to cytokine treatment but also to exposure to bacteria, toxins (Yu and Turner, 2008) or some viruses (Coyne et al, 2007;Liu et al, 2009). This endocytosis coincides with and is required for barrier disruption, since blocking endocytosis prevents cytokine-or toxin-induced increases in tight junction permeability (Shen and Turner, 2005;Clayburgh et al, 2005;Schwarz et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Occludin is required for cytokine-induced regulation of tight junction barriers

Itallie

Fanning

Holmes

et al. 2010

Journal of Cell Science

175

173

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SummaryThe function of occludin remains elusive. Proposed roles include maintenance of tight junction barriers, signaling and junction remodeling. To investigate a potential role in mediating cytokine-induced changes in barrier properties, we measured barrier responses to interferon- plus TNF in control, occludin-overexpressing and occludin knockdown MDCK II monolayers. MDCK cells show a complex response to cytokines characterized by a simultaneous increase in the transepithelial electrical resistance and a decrease in the barrier for large solutes. We observed that overexpression of occludin increased and occludin knockdown decreased sensitivity to cytokines as assessed by both these parameters. It is known that caveolin-1 interacts with occludin and is implicated in several models of cytokine-dependent barrier disruption; we found that occludin knockdown altered the subcellular distribution of caveolin-1 and that partitioning of caveolin into detergent-insoluble lipid rafts was influenced by changing occludin levels. Knockdown of caveolin decreased the cytokine-induced flux increase, whereas the increase in the electrical barrier was unaltered; the effect of double knockdown of occludin and caveolin was similar to that of occludin single knockdown, consistent with the possibility that they function in the same pathway. These results demonstrate that occludin is required for cells to transduce cytokine-mediated signals that either increase the electrical barrier or decrease the large solute barrier, possibly by coordinating the functions of caveolin-1.

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“…Rab5 and its effectors have been shown to facilitate different endocytic pathways, including macropinocytosisinduced membrane ruffling (32). Rab5 signals were also recruited specifically to the internalized macropinosomes when induced by receptor tyrosine kinases (32)(33)(34)(35). Hence, we determined the effect of EphA2 shRNA on the internalization of KSHV in Rab5-positive macropinosomes.…”

Section: Epha2 Regulates Productive Macropinocytosis Of Kshv In Hmvec-dmentioning

confidence: 99%

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

Chakraborty

Veettil

Bottero

et al. 2012

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

157

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Kaposi's sarcoma-associated herpesvirus (KSHV), etiologically associated with Kaposi's sarcoma, uses integrins (α3β1, αVβ3, and αVβ5) and associated signaling to enter human dermal microvascular endothelial cells (HMVEC-d), an in vivo target of infection. KSHV infection activated c-Cbl, which induced the selective translocation of KSHV into lipid rafts (LRs) along with the α3β1, αVβ3, and xCT receptors, but not αVβ5. LR-translocated receptors were monoubiquitinated, leading to productive macropinocytic entry, whereas non-LR-associated αVβ5 was polyubiquitinated, leading to clathrin-mediated entry that was targeted to lysosomes. Because the molecule(s) that integrate signal pathways and productive KSHV macropinocytosis were unknown, we immunoprecipitated KSHV-infected LR fractions with anti-α3β1 antibodies and analyzed them by mass spectrometry. The tyrosine kinase EphrinA2 (EphA2), implicated in many cancers, was identified in this analysis. EphA2 was activated by KSHV. EphA2 was also associated with KSHV and integrins (α3β1 and αVβ3) in LRs early during infection. Preincubation of virus with soluble EphA2, knockdown of EphA2 by shRNAs, or pretreatment of cells with anti-EphA2 monoclonal antibodies or tyrosine kinase inhibitor dasatinib significantly reduced KSHV entry and gene expression. EphA2 associates with c-Cbl-myosin IIA and augmented KSHV-induced Src and PI3-K signals in LRs, leading to bleb formation and macropinocytosis of KSHV. EphA2 shRNA ablated macropinocytosis-associated signaling events, virus internalization, and productive nuclear trafficking of KSHV DNA. Taken together, these studies demonstrate that the EphA2 receptor acts as a master assembly regulator of KSHV-induced signal molecules and KSHV entry in endothelial cells and suggest that the EphA2 receptor is an attractive target for controlling KSHV infection.virus entry | productive endocytosis | receptor tyrosine kinase

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Coxsackievirus Entry across Epithelial Tight Junctions Requires Occludin and the Small GTPases Rab34 and Rab5

Cited by 211 publications

References 50 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

Occludin is required for cytokine-induced regulation of tight junction barriers

Kaposi’s sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection

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