Dengue 2 infection of HepG2 liver cells results in endoplasmic reticulum stress and induction of multiple pathways of cell death

Thepparit, Chutima; Khakpoor, Atefeh; Khongwichit, Sarawut; Wikan, Nitwara; Fongsaran, Chanida; Chingsuwanrote, Pimjai; Panraksa, Patcharee; Smith, Duncan R.

doi:10.1186/1756-0500-6-372

Cited by 51 publications

(44 citation statements)

References 92 publications

(146 reference statements)

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“…Colocalization between DENV 2 E protein and GRP78 has been previously reported1629, and to confirm this as well as provide evidence on the possible colocalization between DENV 4 E protein and GRP78, HEK293T/17 cells were mock-infected or infected with DENV 2 or DENV 4 and at 1 d.p.i. cells were collected and examined under a confocal microscope after staining with antibodies against DENV E protein and GRP78.…”

Section: Resultssupporting

confidence: 76%

“…Studies have previously shown increased expression of GRP78 during DENV infection162029. To confirm this, as well as to investigate the expression of VDAC during infection, HEK293T/17 cells were mock-infected or infected with DENV 2 or DENV 4 and levels of GRP78 and VDAC determined on days 1–3 p.i by western blotting.…”

Section: Resultsmentioning

confidence: 85%

“…Studies have shown that apoptosis is a common consequence of DENV infection of mammalian cells and a number of mechanisms including both intrinsic and extrinsic apoptosis pathways have been proposed293536373839. In intrinsic apoptosis, cytochrome C is released from mitochondria as a consequence of dysregulation of the mitochondrial membrane potential leading to formation of the apoptosome and subsequent induction of apoptosis40.…”

Section: Discussionmentioning

confidence: 99%

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Involvement of voltage-dependent anion channel (VDAC) in dengue infection

Jitobaom

Tongluan

Smith

2016

Sci Rep

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During infection, dengue virus (DENV) proteins interact with host cellular constituents promoting the remodeling of the cell to facilitate virus production. While a number of interacting proteins have been identified for DENV non-structural proteins, far fewer interacting partners have been identified for the DENV structural proteins. One protein that has been identified as a DENV E protein interacting protein is the cellular chaperone GRP78. GRP78 has been shown to have a number of cellular interacting partners including the voltage-dependent anion channel (VDAC). In this study we confirmed the interactions between GRP78 and DENV E protein and between GRP78 and VDAC. VDAC was shown to be re-localized during DENV infection, with no change in levels of protein expression. VDAC is predominantly located on the outer membrane of mitochondria and our result is consistent with movement of the mitochondria towards the ER during DENV infection. Down regulation of VDAC through siRNA significantly reduced DENV protein expression, as well as the percentage infection and output virus titer. Our results suggest that VDAC plays an important role in DENV infection.

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Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Involvement of voltage-dependent anion channel (VDAC) in dengue infection

Jitobaom

Tongluan

Smith

2016

Sci Rep

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“…There are several possible explanations for this discrepancy. However, this simply may reflect that activation of apoptosis is complex and can be triggered through multiple pathways depending on experimental conditions such as MOI and tissue type (Klomporn et al , 2011; McLean et al , 2011; Pattanakitsukul et al , 2007; Theparrit, et al , 2013; Zargar et al , 2011). We note that in Ocampo et al both the range of titers of DENV used for infection and corresponding oral susceptibility seen with their refractory and susceptible strains were higher than those used in our study.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis-related genes control autophagy and influence DENV-2 infection in the mosquito vector, Aedes aegypti

Eng

Zuylen

Severson

2016

Insect Biochemistry and Molecular Biology

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The mosquito Aedes aegypti is the primary urban vector for dengue virus (DENV) worldwide. Insight into interactions occurring between host and pathogen is important in understanding what factors contribute to vector competence. However, many of the molecular mechanisms for vector competence remain unknown. Our previous global transcriptional analysis suggested that differential expression of apoptotic proteins is involved in determining refractoriness vs susceptibility to DENV-2 infection in Ae. aegypti females following a DENV-infected blood meal. To determine whether DENV-refractory Ae. aegypti showed more robust apoptosis upon infection, we compared numbers of apoptotic cells from midguts of refractory and susceptible strains and observed increased numbers of apoptotic cells in only the refractory strain upon DENV-2 infection. Thereafter, we manipulated apoptosis through dsRNA interference of the initiator caspase, Aedronc. Unexpectedly, dsAedronc-treated females showed both decreased frequency of disseminated infection and decreased virus titer in infected individuals. Insect caspases have also previously been identified as regulators of the cellular recycling process known as autophagy. We observed activation of autophagy in midgut and fat body tissues following a blood meal, as well as programmed activation of several apoptosis-related genes, including the effector caspase, Casps7. To determine whether autophagy was affected by caspase knockdown, we silenced Aedronc and Casps7, and observed reduced activation of autophagy upon silencing. Our results provide evidence that apoptosis-related genes are also involved in regulating autophagy, and that Aedronc may play an important role in DENV-2 infection success in Ae. aegypti, possibly through its regulation of autophagy.

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“…Also, in liver cells infected with DENV2, it was observed that PERK and ATF6 were not associated with BiP, resulting in increased eIF-2α phosphorylation (Thepparit et al, 2013). …”

Section: Cellular Stress Pathwaysmentioning

confidence: 99%

Interplay between Inflammation and Cellular Stress Triggered by Flaviviridae Viruses

2016

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The Flaviviridae family comprises several human pathogens, including Dengue, Zika, Yellow Fever, West Nile, Japanese Encephalitis viruses, and Hepatitis C Virus. Those are enveloped, single-stranded positive sense RNA viruses, which replicate mostly in intracellular compartments associated to endoplasmic reticulum (ER) and Golgi complex. Virus replication results in abundant viral RNAs and proteins, which are recognized by cellular mechanisms evolved to prevent virus infection, resulting in inflammation and stress responses. Virus RNA molecules are sensed by Toll-like receptors (TLRs), RIG-I-like receptors (RIG-I and MDA5) and RNA-dependent protein kinases (PKR), inducing the production of inflammatory mediators and interferons. Simultaneously, the synthesis of virus RNA and proteins are distinguished in different compartments such as mitochondria, ER and cytoplasmic granules, triggering intracellular stress pathways, including oxidative stress, unfolded protein response pathway, and stress granules assembly. Here, we review the new findings that connect the inflammatory pathways to cellular stress sensors and the strategies of Flaviviridae members to counteract these cellular mechanisms and escape immune response.

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Dengue 2 infection of HepG2 liver cells results in endoplasmic reticulum stress and induction of multiple pathways of cell death

Cited by 51 publications

References 92 publications

Involvement of voltage-dependent anion channel (VDAC) in dengue infection

Involvement of voltage-dependent anion channel (VDAC) in dengue infection

Apoptosis-related genes control autophagy and influence DENV-2 infection in the mosquito vector, Aedes aegypti

Interplay between Inflammation and Cellular Stress Triggered by Flaviviridae Viruses

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