Porcine parvovirus infection activates mitochondria-mediated apoptotic signaling pathway by inducing ROS accumulation

Zhao, Xiaomin; Xiang, Hailing; Bai, Xiaoyuan; Fei, Naijiao; Huang, Yong; Song, Xiangjun; Zhang, Hongling; Zhang, Liang; Tong, Dewen

doi:10.1186/s12985-016-0480-z

Cited by 34 publications

(30 citation statements)

References 31 publications

(37 reference statements)

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“…In the case of PPV, it was reported that the YL strain induces apoptosis in ST and PK-15 cells and in the late phase of infection (60 h p.i.) the number of apoptotic cells can reach 50% (35,36). In contrast, during Kresse strain infection in PT cells, the number of apoptotic cells remained low, as indicated by the number of pyknotic and karyorrhectic nuclei, and it never exceeded 14%, regardless of the presence or absence of SATp.…”

Section: Discussionmentioning

confidence: 99%

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

Mészáros

Tóth

Olasz

et al. 2017

J Virol

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The SAT protein (SATp) of porcine parvovirus (PPV) accumulates in the endoplasmic reticulum (ER), and SAT deletion induces the slow-spreading phenotype. The in vitro comparison of the wild-type Kresse strain and its SAT knockout (SAT Ϫ ) mutant revealed that prolonged cell integrity and late viral release are responsible for the slower spreading of the SAT Ϫ virus. During PPV infection, regardless of the presence or absence of SATp, the expression of downstream ER stress response proteins (Xbp1 and CHOP) was induced. However, in the absence of SATp, significant differences in the quantity and the localization of CHOP were detected, suggesting a role of SATp in the induction of irreversible ER stress in infected cells. The involvement of the induction of irreversible ER stress in porcine testis (PT) cell necrosis and viral egress was confirmed by treatment of infected cells by ER stressinducing chemicals (MG132, dithiothreitol, and thapsigargin), which accelerated the egress and spreading of both the wild-type and the SAT Ϫ viruses. UV stress induction had no beneficial effect on PPV infection, underscoring the specificity of ER stress pathways in the process. However, induction of CHOP and its nuclear translocation cannot alone be responsible for the biological effect of SAT, since nuclear CHOP could not complement the lack of SAT in a coexpression experiment. IMPORTANCE SATp is encoded by an alternative open reading frame of the PPV genome. Earlier we showed that SATp of the attenuated PPV NADL-2 strain accumulates in the ER and accelerates virus release and spreading. Our present work revealed that slow spreading is a general feature of SAT Ϫ PPVs and is the consequence of prolonged cell integrity. PPV infection induced ER stress in infected cells regardless of the presence of SATp, as demonstrated by the morphological changes of the ER and expression of the stress response proteins Xbp1 and CHOP. However, the presence of SATp made the ER stress more severe and accelerated cell death during infection, as shown by the higher rate of expression of CHOP and alteration of the localization of CHOP. The beneficial effect of irreversible ER stress on PPV spread was confirmed by treatment of infected cells with ER stress-inducing chemicals.KEYWORDS CHOP, ER stress, SAT, Xbp1, alternative ORF, parvovirus, protoparvovirus, viral egress P orcine parvovirus (PPV) belongs to the species Ungulate protoparvovirus 1 in the genus Protoparvovirus. It is the causative agent of the stillbirth, mummification, embryonic death, infertility (SMEDI) syndrome in swine (1).A highly pathogenic strain with broad tissue tropism, strain Kresse, was isolated in the 1980s (2, 3). Kresse strain-infected piglets showed atypical signs of PPV infection, including necrotic lesions (4) on the lips, snout, tongue, and foot.The PPV single-stranded genome contains two major open reading frames (ORFs)

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Section: Discussionmentioning

confidence: 99%

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

Mészáros

Tóth

Olasz

et al. 2017

J Virol

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“…In the present study, PEDV disturbed the homeostatic balance between the generation and elimination of ROS, leading to the accumulation of ROS at every corresponding time after infection. Accumulating evidence from some studies has revealed that ROS are related to apoptosis in many viral infections (Hristov et al, 2010;Zhao et al, 2016;Tung et al, 2010). Since ROS were accumulated during PEDV infection, further studies should be undertaken to determine whether ROS are related to apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…For example, parvovirus H-1 infection induces apoptosis via mediating ROS accumulation (Hristov et al, 2010). PPV infection induces ST cells apoptosis via activation of ROS generation and mitochondria-mediated apoptotic signalling (Zhao et al, 2016). ROS have also been implicated in some important apoptotic signalling pathways, such as p38 MAPK and p53 pathways (Fuh et al, 2002;Hamanaka and Chandel, 2010).…”

Section: Introductionmentioning

confidence: 99%

Porcine epidemic diarrhea virus infections induce apoptosis in Vero cells via a reactive oxygen species (ROS)/p53, but not p38 MAPK and SAPK/JNK signalling pathways

Xü

Zhang

et al. 2019

Veterinary Microbiology

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Porcine epidemic diarrhea virus (PEDV) is a member of Coronavirus, which causes severe watery diarrhea in piglets with high morbidity and mortality. ROS and p53 play key roles in regulating many kinds of cell process during viral infection, however, the exact function in PEDV-induced apoptosis remains unclear. In this study, the pro-apoptotic effect of PEDV was examined in Vero cells and we observed that PEDV infection increased MDM2 and CBP, promoted p53 phosphorylation at serine 20 and, promoted p53 nuclear translocation, leading to p53 activation in Vero cells. Treatment with the p53 inhibitor PFT-α could significantly inhibit PEDV-induced apoptosis. We also observed PEDV infection induced time-dependent ROS accumulation. Treatment with antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine (NAC), significantly inhibited PEDVinduced apoptosis.Moreover, further inhibition tests were established to prove that p53 was regulated by ROS in PEDV-induced apoptosis. In addition, we also found that p38 MAPK and SAPK/JNK were activated in PEDV-infected Vero cells. However, treatment with the p38 MAPK inhibitor SB203580, and the SAPK/JNK inhibitor SP600125 reversed PEDV-induced apoptosis. Taken together, the results of this study demonstrate that activated p53 and accumulated ROS participated in PEDV-induced apoptosis and p53 could be regulated by ROS during PEDV infection. Activated p38 MAPK and SAPK/JNK exerted no influence on PEDV-induced apoptosis. These findings provide new insights into the function of p53 and ROS in the interaction of PEDV with Vero cells.

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“…Previous studies have reported that PPV infection can induce apoptosis through the activation of mitogen protein kinases, p53, and mitochondria-mediated pathway (Zhao et al, 2016;Zheng et al, 2018). Nutlin-3 is an agonist that can induce p53-and caspase-dependent cell apoptosis (Thompson et al, 2004;Vassilev et al, 2004).…”

Section: Ppv-induced Er Stress Accelerates Apoptotic Cell Death and Smentioning

confidence: 99%

Porcine parvovirus replication is suppressed by activation of the PERK signaling pathway and endoplasmic reticulum stress-mediated apoptosis

et al. 2020

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Keywords:Porcine parvovirus Endoplasmic reticulum stress Unfolded protein response Protein kinase R-like ER kinase pathway Apoptotic cell death A B S T R A C T Endoplasmic reticulum (ER) stress is associated with numerous mammalian diseases, especially viral diseases. Porcine parvovirus (PPV) is the causative agent of reproductive failure in swine. Here, we observed that the PPV infection of porcine kidney 15 and porcine testis cells resulted in the activation of ER stress sensors mediated by protein kinase R-like ER kinase (PERK), but not inositol-requiring enzyme 1 and activating transcription factor 6 (ATF6). ER stress activation obviously blocked PPV replication. Depletion of proteins, such as PERK, eukaryotic initiation factor 2, and ATF4, by small interfering RNA significantly enhanced PPV replication. Moreover, the pro-apoptotic factor C/EBP homologous protein was identified a key factor in the inhibition of PPV replication. These data demonstrate that PPV infection activates ER stress through the PERK signaling pathway and that ER stress inhibits further PPV replication by promoting apoptosis.

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Porcine parvovirus infection activates mitochondria-mediated apoptotic signaling pathway by inducing ROS accumulation

Cited by 34 publications

References 31 publications

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

Porcine epidemic diarrhea virus infections induce apoptosis in Vero cells via a reactive oxygen species (ROS)/p53, but not p38 MAPK and SAPK/JNK signalling pathways

Porcine parvovirus replication is suppressed by activation of the PERK signaling pathway and endoplasmic reticulum stress-mediated apoptosis

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