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

Harris, Katharine G.; Coyne, Carolyn B.

doi:10.1016/j.cytogfr.2014.08.002

Cited by 24 publications

(21 citation statements)

References 117 publications

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“…CVB is known to extensively interact with and antagonize host cell pathways through various mechanisms, including via the activity of two virally-encoded proteases, 2A pro and 3C pro (Harris and Coyne, 2013, 2014). Although we found that RIP3 was involved in the facilitation of CVB replication in IECs by promoting autophagy, RIP3 is also a key component in the pro-inflammatory necrotic cell death pathway, which may be detrimental to CVB replication.…”

Section: Resultsmentioning

confidence: 99%

RIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells

Harris

Morosky

Drummond

et al. 2015

Cell Host & Microbe

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Summary Receptor Interacting Protein Kinase-3 (RIP3) is an essential kinase for necroptotic cell death signaling and has been implicated in antiviral cell death signaling upon DNA virus infection. Here, we performed high-throughout RNAi screening and identified RIP3 as a positive regulator of coxsackievirus B3 (CVB) replication in intestinal epithelial cells (IECs). RIP3 regulates autophagy, a process utilized by CVB for viral replication factory assembly, and depletion of RIP3 inhibits autophagic flux and leads to the accumulation of autophagosomes and amphisomes. Additionally, later in infection, RIP3 is cleaved by the CVB-encoded cysteine protease 3Cpro, which serves to abrogate RIP3-mediated necrotic signaling and induce a non-necrotic form of cell death. Taken together, our results show that temporal targeting of RIP3 allows CVB to benefit from its roles in regulating autophagy while inhibiting the induction of necroptotic cell death.

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Section: Resultsmentioning

confidence: 99%

RIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells

Harris

Morosky

Drummond

et al. 2015

Cell Host & Microbe

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“…However, factors including the virus strain and the infected cell type could contribute to the variability of CPEs. Previous studies have suggested that different enterovirus-specific proteins play regulatory roles in virus-induced CPEs (24). Host-specific factors that regulate apoptotic and cytokine/chemokine production pathways may also modulate CPEs and virus production independently (25,26).…”

Section: Discussionmentioning

confidence: 99%

Human tryptophanyl-tRNA synthetase is an IFN-γ–inducible entry factor for Enterovirus

Yeung¹,

Jia²,

Yip³

et al. 2018

Journal of Clinical Investigation

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Enterovirus A71 (EV-A71) receptors that have been identified to date cannot fully explain the pathogenesis of EV-A71, which is an important global cause of hand, foot, and mouth disease and life-threatening encephalitis. We identified an IFN-γ-inducible EV-A71 cellular entry factor, human tryptophanyl-tRNA synthetase (hWARS), using genome-wide RNAi library screening. The importance of hWARS in mediating virus entry and infectivity was confirmed by virus attachment, in vitro pulldown, antibody/antigen blocking, and CRISPR/Cas9-mediated deletion. Hyperexpression and plasma membrane translocation of hWARS were observed in IFN-γ-treated semipermissive (human neuronal NT2) and cDNA-transfected nonpermissive (mouse fibroblast L929) cells, resulting in their sensitization to EV-A71 infection. Our hWARS-transduced mouse infection model showed pathological changes similar to those seen in patients with severe EV-A71 infection. Expression of hWARS is also required for productive infection by other human enteroviruses, including the clinically important coxsackievirus A16 (CV-A16) and EV-D68. This is the first report to our knowledge on the discovery of an entry factor, hWARS, that can be induced by IFN-γ for EV-A71 infection. Given that we detected high levels of IFN-γ in patients with severe EV-A71 infection, our findings extend the knowledge of the pathogenicity of EV-A71 in relation to entry factor expression upon IFN-γ stimulation and the therapeutic options for treating severe EV-A71-associated complications.

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“…CVB also can antagonize the apoptotic pathway in cells, allowing viral replication to proceed for a longer amount of time necessary to maximize progeny (Harris & Coyne, 2014). For example, CVB can cleave cell components of the pro-apoptotic family, including TRIF (Mukherjee, Morosky et al, 2011), and viral 2B protein can act as viroporin disrupting Ca 2+ gradients necessary to initiate apoptosis (Campanella, de Jong et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Recent progress in understanding coxsackievirus replication, dissemination, and pathogenesis

et al. 2015

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Coxsackieviruses (CVs) are relatively common viruses associated with a number of serious human diseases, including myocarditis and meningo-encephalitis. These viruses are considered cytolytic yet can persist for extended periods of time within certain host tissues requiring evasion from the host immune response and a greatly reduced rate of replication. A member of Picornaviridae family, CVs have been historically considered non-enveloped viruses – although recent evidence suggest that CV and other picornaviruses hijack host membranes and acquire an envelope. Acquisition of an envelope might provide distinct benefits to CV virions, such as resistance to neutralizing antibodies and efficient nonlytic viral spread. CV exhibits a unique tropism for progenitor cells in the host which may help to explain the susceptibility of the young host to infection and the establishment of chronic disease in adults. CVs have also been shown to exploit autophagy to maximize viral replication and assist in unconventional release from target cells. In this article, we review recent progress in clarifying virus replication and dissemination within the host cell, identifying determinants of tropism, and defining strategies utilized by the virus to evade the host immune response. Also, we will highlight unanswered questions and provide future perspectives regarding the potential mechanisms of CV pathogenesis.

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

Cited by 24 publications

References 117 publications

RIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells

RIP3 Regulates Autophagy and Promotes Coxsackievirus B3 Infection of Intestinal Epithelial Cells

Human tryptophanyl-tRNA synthetase is an IFN-γ–inducible entry factor for Enterovirus

Recent progress in understanding coxsackievirus replication, dissemination, and pathogenesis

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