Autophagy Benefits the Replication of Newcastle Disease Virus in Chicken Cells and Tissues

Sun, Yingjie; Yu, Shuang; Ding, Na; Chen, Meng; Shao, Meng; Zhang, Shilei; Zhan, Yuan; Qiu, Xusheng; Tan, Lei; Chen, Hongjun; Chen, Song; Ding, Chan

doi:10.1128/jvi.01849-13

Cited by 103 publications

(104 citation statements)

References 55 publications

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“…A similar result was observed in the U251 glioma and chicken cells infected with NDV Beaudette C strain [32, 33]. However, the precise mechanisms by which autophagy promote viral replication remains unclear.…”

Section: Discussionsupporting

confidence: 78%

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Mitophagy promotes replication of oncolytic Newcastle disease virus by blocking intrinsic apoptosis in lung cancer cells

Mao

Wang

et al. 2014

Oncotarget

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Apoptosis contributes to antitumor effect of Newcastle disease virus (NDV). Autophagy is a protective response under cellular stress including viral infection. How autophagy interferes with oncolysis of NDV remains unclear. In this study, we found that NDV La Sota strain induced autophagy and preserved autophagic flux in non-small cell lung cancer cells. NDV-induced autophagy promoted viral replication by blocking cancer cells from caspase-dependent apoptosis. Moreover, we found that NDV recruited SQSTM1-mediated mitophagy to control cytochrome c release, and thus blocked intrinsic pro-apoptotic signaling. Finally, we observed an enhanced oncolysis in NSCLC cells treated with NDV in the presence of an autophagy inhibitor 3-methyladenine (3-MA). Interestingly, a more profound antitumor effect could be achieved when administration of 3-MA was postponed to 24 h after NDV infection. Our findings unveil a novel way that NDV subverts mitophagy to favor its replication by blocking apoptosis, and provide rationale for systemic therapeutic cohort combining NDV with autophagy inhibitors in cancer therapy.

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Section: Discussionsupporting

confidence: 78%

“…It has been shown recently that NDV strain Beaudette C triggers autophagy both in human U251 glioma cells and in chicken cells leading to enhanced virus replication [32, 33]. However, it remains unclear how autophagy promotes viral replication.…”

Section: Introductionmentioning

confidence: 99%

Mitophagy promotes replication of oncolytic Newcastle disease virus by blocking intrinsic apoptosis in lung cancer cells

Mao

Wang

et al. 2014

Oncotarget

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“…The intracellular loads of pVP2 were similar with and without rapamycin treatment, but the intracellular and extracellular virus titers increased significantly in the presence of rapamycin (data not shown). A previous study showed that rapamycin does not induce obvious autophagy in DF-1 cells as it does in mammalian cells (32). Cells were starved of amino acids, a condition also known to induce autophagy (40).…”

Section: Resultsmentioning

confidence: 97%

“…Avian reovirus nonstructural protein p17 induces autophagy, resulting in enhanced virus replication (31). Furthermore, autophagy is beneficial to the replication of Newcastle disease virus in both chicken cells and tissues (32). These data highlight the remarkable diversity in term of strategies by which viruses subvert the autophagy pathway and raise the possibility that autophagic degradation could itself promote virus production.…”

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confidence: 92%

Infectious Bursal Disease Virus Subverts Autophagic Vacuoles To Promote Viral Maturation and Release

Wang

Duan

Han

et al. 2017

J Virol

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Autophagy functions as an intrinsic antiviral defense. However, some viruses can subvert or even enhance host autophagic machinery to increase viral replication and pathogenesis. The role of autophagy during avibirnavirus infection, especially late stage infection, remains unclear. In this study, infectious bursal disease virus (IBDV) was used to investigate the role of autophagy in avibirnavirus replication. We demonstrated IBDV induction of autophagy as a significant increase in puncta of LC3 ϩ autophagosomes, endogenous levels of LC3-II, and ultrastructural characteristics typical of autophagosomes during the late stage of infection. Induction of autophagy enhances IBDV replication, whereas inhibition of autophagy impairs viral replication. We also demonstrated that IBDV infection induced autophagosome-lysosome fusion, but without active degradation of their contents. Moreover, inhibition of fusion or of lysosomal hydrolysis activity significantly reduced viral replication, indicating that virions utilized the low-pH environment of acidic organelles to facilitate viral maturation. Using immuno-transmission electron microscopy (TEM), we observed that a large number of intact IBDV virions were arranged in a lattice surrounded by p62 proteins, some of which lay between virions. Additionally, many virions were encapsulated within the vesicular membranes, with an obvious release stage observed by TEM. The autophagic endosomal pathway facilitates low-pH-mediated maturation of viral proteins and membrane-mediated release of progeny virions.IMPORTANCE IBDV is the most extensively studied virus in terms of molecular characteristics and pathogenesis; however, mechanisms underlying the IBDV life cycle require further exploration. The present study demonstrated that autophagy enhances viral replication at the late stage of infection, and the autophagy pathway facilitates IBDV replication complex function and virus assembly, which is critical to completion of the virus life cycle. Moreover, the virus hijacks the autophagic vacuoles to mature in an acidic environment and release progeny virions in a membrane-mediated cellto-cell manner. This autophagic endosomal pathway is proposed as a new mechanism that facilitates IBDV maturation, release, and reinternalization. This report presents a concordance in exit strategies among some RNA and DNA viruses, which exploit autophagy pathway for their release from cells.

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“…They used the ptfLC3 plasmid to show that siRNA knockdown of GAPR-1, a newly identified inhibitor of autophagy, increased autophagosome formation by causing an increase in autophagic flux rather than a block in autophagosome maturation. Another group studied of the role of autophagy in Newcastle Disease Virus (NDV) infection (38). This study showed that NDV infection induces autophagic flux in two different kinds of chicken cells.…”

Section: Discussionmentioning

confidence: 99%

Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection

Buckingham

Carpenter

Jackson

et al. 2014

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

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Autophagy is a process by which misfolded and damaged proteins are sequestered into autophagosomes, before degradation in and recycling from lysosomes. We have extensively studied the role of autophagy in varicella-zoster virus (VZV) infection, and have observed that vesicular cells are filled with >100 autophagosomes that are easily detectable after immunolabeling for the LC3 protein. To confirm our hypothesis that increased autophagosome formation was not secondary to a block, we examined all conditions of VZV infection as well as carrying out two assessments of autophagic flux. We first investigated autophagy in human skin xenografts in the severe combined immunodeficiency (SCID) mouse model of VZV pathogenesis, and observed that autophagosomes were abundant in infected human skin tissues. We next investigated autophagy following infection with sonically prepared cell-free virus in cultured cells. Under these conditions, autophagy was detected in a majority of infected cells, but was much less than that seen after an infected-cell inoculum. In other words, inoculation with lower-titered cell-free virus did not reflect the level of stress to the VZV-infected cell that was seen after inoculation of human skin in the SCID mouse model or monolayers with higher-titered infected cells. Finally, we investigated VZVinduced autophagic flux by two different methods (radiolabeling proteins and a dual-colored LC3 plasmid); both showed no evidence of a block in autophagy. Overall, therefore, autophagy within a VZV-infected cell was remarkably different from autophagy within an HSV-infected cell, whose genome contains two modifiers of autophagy, ICP34.5 and US11, not present in VZV.V ZV induces macroautophagy (hereafter referred to as autophagy) in skin cells within the typical exanthem associated with either primary VZV infection (varicella or chickenpox) or VZV reactivation (herpes zoster or shingles). During prior studies, the extent of autophagy was gauged by enumeration of autophagosomes by both 2D and 3D microscopy (1, 2). The usual number of autophagosomes seen by 3D animation was 100 per infected cell, but sometimes approached 200 per cell. In contrast, a typical nonstressed cell usually has fewer than 4 autophagosomes (3, 4). When monolayers were inoculated with VZV-infected cells, the traditional method for VZV infection, autophagy was again easily seen after enumeration of autophagosomes and immunoblotting for the LC3-phosphatidylethanolamine conjugate (LC3-II). Again these results suggested that autophagic flux was present during VZV infection in cultured cells.As part of a more extensive assessment of autophagy after VZV-induced cellular stress, we have now investigated autophagy in infected human skin xenografts from the SCID mouse model of VZV infection. This model is the most accurate representation of the skin manifestation of varicella in the human host (5, 6). Finally, we addressed an important point about the nature of VZV-induced autophagy. Because the number of autophagosomes seen in the human vesicle...

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Autophagy Benefits the Replication of Newcastle Disease Virus in Chicken Cells and Tissues

Cited by 103 publications

References 55 publications

Mitophagy promotes replication of oncolytic Newcastle disease virus by blocking intrinsic apoptosis in lung cancer cells

Mitophagy promotes replication of oncolytic Newcastle disease virus by blocking intrinsic apoptosis in lung cancer cells

Infectious Bursal Disease Virus Subverts Autophagic Vacuoles To Promote Viral Maturation and Release

Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection

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