Abstract
Bovine viral diarrhea (BVD) is a worldwide infectious disease caused by bovine viral diarrhea virus (BVDV) infection, which invades the placenta, causes abortion, produces immune tolerance and continuously infects calves, and causes huge economic losses to the cattle industry. The endoplasmic reticulum (ER) is an important organelle in cells, which is prone to ER stress after being stimulated by pathogens, thus activating the ER stress–related apoptosis. Studies have confirmed that BVDV can utilize the ER of its host to complete its own proliferation and stimulate ER stress to a certain extent. However, the role of ER stress in BVDV infecting bovine placental trophoblast cells (BTCs) and inducing apoptosis is still unclear. We are using the cytopathic strain of BVDV (OregonC24Va), which can cause apoptosis of BTCs, as a model system to determine how ER stress induced by BVDV affects placental toxicity. We show that OregonC24Va can infect BTCs and proliferate in it. With the proliferation of BVDV in BTCs, ER stress–related apoptosis is triggered. The ER stress inhibitor 4-PBA was used to inhibit the ER stress of BTCs, which not only inhibited the proliferation of BVDV, but also reduced the apoptosis of BTCs. The ER stress activator Tg can activate ER stress–related apoptosis, but the proliferation of BVDV does not change in BTCs. Therefore, BVDV utilizes the UPR of activated ER stress to promote the proliferation of BVDV in the early stage of infection, and activates the ER stress–related apoptosis of BTCs in the later stage with the virus proliferation to promote the cell apoptosis and further spread of the virus. Our research provides a new theoretical basis for exploring the placental infection and vertical transmission of BVDV.
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All data generated or analyzed in this study are available from the corresponding author on reasonable request.
Abbreviations
- ER :
-
Endoplasmic reticulum
- BVDV :
-
Bovine viral diarrhea virus
- BVD :
-
Bovine viral diarrhea
- BTCs :
-
Bovine placental trophoblast cells
- CHOP :
-
C/EBP homologous protein
- GRP78 :
-
Glucose-regulated protein, 78 KDa
- UPR :
-
Unfolded protein response
- IRE-1 :
-
Inositol-requiring enzyme1
- ATF6 :
-
Activating transcription factor 6
- PERK :
-
PKR-like ER kinase
- XBP1 :
-
X-box-binding protein
- ERAD :
-
Endoplasmic reticulum–associated degradation
- GADD153 :
-
Growth arrest and DNA-damage inducible gene153
- JNK :
-
C-Jun N-terminal kinase
- PI :
-
Persistently infected
- CP :
-
Cytopathogenic
- NCP :
-
Noncytopathic
- Bcl-2 :
-
B cell lymphoma-2
- ORF :
-
Open reading frame
- IRF-3 :
-
Interferon regulatory factor 3
- Tg :
-
Thapsigargin
- 4-PBA :
-
4-Phenylbutyric acid
- IFN :
-
Interferon
- MDBK :
-
Madin-Darby bovine kidney
- CPE :
-
Cytopathic effect
- WNV :
-
West Nile virus
- IBV :
-
Infectious bronchitis virus
- DEV :
-
Duck enteritis virus
- Bax :
-
BCL2-associated X protein
- Bak :
-
Bcl-2 homologous antagonist/killer
- PRV :
-
Pseudorabies virus
- MDV :
-
Marek’s disease virus
- ZIKV :
-
Zika virus
- DENV :
-
Dengue virus
- eIF2α :
-
Eukaryotic initiation factor 2α
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Acknowledgements
This research was supported by the National Natural Science Foundation of China (NO. 31802263, 31802258) and the Zhejiang Provincial Natural Science Foundation (NO. LY22C18000).
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NHY, QJS, and XGW performed the experiments and collected and interpreted the data. XHS, XLQ, and KX provided initial help with the analysis. ZHZ, ZW, and YJ collected the samples. XGW and NHY conceptualized and wrote the manuscript. LFX reviewed the manuscript prior to publication.
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Yuan, N., Song, Q., Jin, Y. et al. Replication of standard bovine viral diarrhea strain OregonC24Va induces endoplasmic reticulum stress–mediated apoptosis of bovine trophoblast cells. Cell Stress and Chaperones 28, 49–60 (2023). https://doi.org/10.1007/s12192-022-01300-1
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DOI: https://doi.org/10.1007/s12192-022-01300-1