The Interplay of Reovirus with Autophagy

Chiu, Hung-Chuan; Richart, Sarah M.; Lin, Fong‐Yuan; Hsu, Wei‐Li; Liu, Hung-Jen

doi:10.1155/2014/483657

Cited by 11 publications

(10 citation statements)

References 78 publications

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“…These genes work in coordination to regulate autophagy, including the formation of autophagosomes and their fusion with lysosomes [ 10 ]. Under normal conditions, autophagy proceeds at a basal level, but it is markedly activated in response to a variety of extracellular and intracellular stimuli, including nutrient starvation, energy depletion, reactive oxygen stress and microbial infection [ 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Regarding BTV, we speculate that autophagy is likely to be involved in BTV infection based on several experimental clues: (i) In one study, activated host autophagy appeared to inhibit post-BTV infection when cells were treated with two compound agents, C003 and C052 [ 19 ], but a more specialized and systematic verification has not been reported. In addition, another member of the Orbivirus genus, epizootic hemorrhagic disease virus (EHDV), can induce autophagy in cultured mammalian cells [ 20 ]; (ii) Recent research findings have described the modulation of autophagy by mammalian reovirus (MRV) and by avian reovirus (ARV), which both belong to the Reoviridae family and share a similar virus structure [ 13 , 21 , 22 ]; (iii) Finally, crosstalk has been observed between apoptosis and autophagy pathways [ 23 , 24 ]. Exploitation of the host apoptosis pathway is a critical strategy utilized by BTV for its pathological effects, as evidenced by a recent experimental system that demonstrated that BTV infection triggers apoptosis in mammalian cells and that the uncoating of BTV was required for this process [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Autophagy Activated by Bluetongue Virus Infection Plays a Positive Role in Its Replication

Liu

Sun

et al. 2015

Viruses

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Bluetongue virus (BTV) is an important pathogen of wild and domestic ruminants. Despite extensive study in recent decades, the interplay between BTV and host cells is not clearly understood. Autophagy as a cellular adaptive response plays a part in many viral infections. In our study, we found that BTV1 infection triggers the complete autophagic process in host cells, as demonstrated by the appearance of obvious double-membrane autophagosome-like vesicles, GFP-LC3 dots accumulation, the conversion of LC3-I to LC3-II and increased levels of autophagic flux in BSR cells (baby hamster kidney cell clones) and primary lamb lingual epithelial cells upon BTV1 infection. Moreover, the results of a UV-inactivated BTV1 infection assay suggested that the induction of autophagy was dependent on BTV1 replication. Therefore, we investigated the role of autophagy in BTV1 replication. The inhibition of autophagy by pharmacological inhibitors (3-MA, CQ) and RNA interference (siBeclin1) significantly decreased viral protein synthesis and virus yields. In contrast, treating BSR cells with rapamycin, an inducer of autophagy, promoted viral protein expression and the production of infectious BTV1. These findings lead us to conclude that autophagy is activated by BTV1 and contributes to its replication, and provide novel insights into BTV-host interactions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagy Activated by Bluetongue Virus Infection Plays a Positive Role in Its Replication

Liu

Sun

et al. 2015

Viruses

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“…When these cells were pretreated with the autophagy inhibitor 3-methyladenine (3-MA), a fourfold reduction in autophagy was detected at 48 h post reovirus infection [ 57 , 58 ]. Studies involving avian reovirus (ARV) have [ 59 ] into this process. In vitro infection of Vero cells with ARV has shown to induce autophagy via the PI3K/ Akt/mammalian target of rapamycin (mTOR) signaling pathway evidenced by immunoblotting [ 60 ].…”

Section: Mechanisms Of Reovirus-mediated Cell Deathmentioning

confidence: 99%

Oncolytic Viral Therapy Using Reovirus

Thirukkumaran

Morris

2015

Methods in Molecular Biology

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Current mainstays in cancer treatment such as chemotherapy, radiation therapy, hormonal manipulation, and even targeted therapies such as Trastuzumab (herceptin) for breast cancer or Iressa (gefitinib) for non-small cell lung cancer among others are limited by lack of efficacy, cellular resistance, and toxicity. Dose escalation and combination therapies designed to overcome resistance and increase efficacy are limited by a narrow therapeutic index. Oncolytic viruses are one such group of new biological therapeutics that appears to have a wide spectrum of anticancer activity with minimal human toxicity. Since the malignant phenotype of tumors is the culmination of multiple mutations that occur in genes eventually leading to aberrant signaling pathways, oncolytic viruses either natural or engineered specifically target tumor cells taking advantage of this abnormal cellular signaling for their replication. Reovirus is one such naturally occurring double-stranded RNA virus that exploits altered signaling pathways (including Ras) in a myriad of cancers. The ability of reovirus to infect and lyse tumors under in vitro, in vivo, and ex vivo conditions has been well documented previously by us and others. The major mechanism of reovirus oncolysis of cancer cells has been shown to occur through apoptosis with autophagy taking place during this process in certain cancers. In addition, the synergistic antitumor effects of reovirus in combination with radiation or chemotherapy have also been demonstrated for reovirus resistant and moderately sensitive tumors. Recent progress in our understanding of viral immunology in the tumor microenvironment has diverted interest in exploring immunologic mechanisms to overcome resistance exhibited by chemotherapeutic drugs in cancer. Thus, currently several investigations are focusing on immune potentiating of reovirus for maximal tumor targeting. This chapter therefore has concentrated on immunologic cell death induction with reovirus as a novel approach to cancer therapy used under in vitro and in vivo conditions, as well as in a clinical setting. Reovirus phase I clinical trials have shown indications of efficacy, and several phase II/III trials are ongoing at present. Reovirus's extensive preclinical efficacy, replication competency, and low toxicity profile in humans have placed it as an attractive anticancer therapeutic for ongoing clinical testing that are highlighted in this chapter.

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“…A fourfold reduction in autophagy by 48 h of reovirus infection was demonstrated when RPMI 8226 cells were pre-treated with the autophagy inhibitor 3-methyladenine (3-MA) ( 64 ). Understanding of the mechanisms behind mammalian reovirus-induced autophagy is limited to the above studies; however, in vitro studies involving avian reovirus (ARV) have provided further insight ( 66 , 67 ). ARV infection of Vero cells in vitro induced autophagy via PI3K/Akt/mammalian target of rapamycin (mTOR) signaling detected by immunoblotting ( 67 ).…”

Section: Mechanism Of Oncolysismentioning

confidence: 99%

Activated Ras Signaling Pathways and Reovirus Oncolysis: An Update on the Mechanism of Preferential Reovirus Replication in Cancer Cells

Gong

Mita

2014

Front. Oncol.

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The development of wild-type, unmodified Type 3 Dearing strain reovirus as an anticancer agent has currently expanded to 32 clinical trials (both completed and ongoing) involving reovirus in the treatment of cancer. It has been more than 30 years since the potential of reovirus as an anticancer agent was first identified in studies that demonstrated the preferential replication of reovirus in transformed cell lines but not in normal cells. Later investigations have revealed the involvement of activated Ras signaling pathways (both upstream and downstream) and key steps of the reovirus infectious cycle in promoting preferential replication in cancer cells with reovirus-induced cancer cell death occurring through necrotic, apoptotic, and autophagic pathways. There is increasing evidence that reovirus-induced antitumor immunity involving both innate and adaptive responses also contributes to therapeutic efficacy though this discussion is beyond the scope of this article. Here, we review our current understanding of the mechanism of oncolysis contributing to the broad anticancer activity of reovirus. Further understanding of reovirus oncolysis is critical in enhancing the clinical development and efficacy of reovirus.

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The Interplay of Reovirus with Autophagy

Cited by 11 publications

References 78 publications

Autophagy Activated by Bluetongue Virus Infection Plays a Positive Role in Its Replication

Autophagy Activated by Bluetongue Virus Infection Plays a Positive Role in Its Replication

Oncolytic Viral Therapy Using Reovirus

Activated Ras Signaling Pathways and Reovirus Oncolysis: An Update on the Mechanism of Preferential Reovirus Replication in Cancer Cells

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