猪肠道α冠状病毒感染增加脂滴的积聚促进病毒复制

doi:10.1016/j.jia.2023.10.010

Journal of Integrative Agriculture ›› 2024, Vol. 23 ›› Issue (3): 988-1005.DOI: 10.1016/j.jia.2023.10.010

猪肠道α冠状病毒感染增加脂滴的积聚促进病毒复制

收稿日期:2023-04-03 接受日期:2023-08-29 出版日期:2024-03-20 发布日期:2024-03-03

Porcine enteric alphacoronavirus infection increases lipid droplet accumulation to facilitate the virus replication

Qi Gao^{1, 2, 3}, Yongzhi Feng^{1, 3}, Ting Gong^{1, 4}, Dongdong Wu^{1, 4}, Xiaoyu Zheng^{1, 3}, Yizhuo Luo^{1, 2}, Yunlong Yang^{1, 2}, Zebu Song^{1, 4}, Lang Gong^{1, 2, 4#}, Guihong Zhang^{1, 4#}

¹ Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China
² Maoming Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Maoming 525000, China
³ Key Laboratory of Animal Vaccine Development, Ministry of Agriculture and Rural Affairs, Guangzhou 510000, China
⁴ Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China

Received:2023-04-03 Accepted:2023-08-29 Online:2024-03-20 Published:2024-03-03
About author:Qi Gao, E-mail: qigao2021@scau.edu.cn; #Correspondence Guihong Zhang, E-mail: guihongzh@scau.edu.cn; Lang Gong, E-mail: gonglang@scau.edu.cn
Supported by:
This research was funded by the National Natural Science Foundation of China (32102646), the Natural Science Foundation of Guangdong Province, China (2020A1515110315), the Start-up Research Project of Maoming Laboratory, China (2021TDQD002), and the China Agriculture Research System of MOF and MARA (cars-35).

摘要/Abstract

摘要：

冠状病毒具有广泛的宿主范围，可以在人和动物之间传播，并引起不同严重程度的疾病。猪肠道甲型冠状病毒(Porcine enteric alphacoronavirus, PEAV) 于2017年首次在中国广东被报道，它是近几年新发现的猪肠道致病性冠状病毒，可导致新生仔猪发生水样腹泻。由于对PEAV的宿主免疫应答、炎症反应和致病机制尚无深入研究的报道，因此急需对PEAV的感染与复制机制进行探究。本研究通过对PEAV感染宿主细胞的转录组学进行分析，发现PEAV可以上调宿主的脂质代谢途径。在脂质代谢、能量稳态等过程中，脂滴(lipid droplets, LD)是具有主要功能的细胞器，同时LD在病毒感染和炎症反应中具有重要作用。在本研究中，我们探究了LD的积聚对宿主炎症反应以及PEAV复制的影响。在受感染的细胞中发现，PEAV增加LD的积聚，并可以上调NF-κB信号通路、促进炎症因子IL-1β和IL-8的产生以及诱导细胞死亡。通过使用DGAT-1 inhibitor抑制LD的积聚可显著抑制PEAV的复制、下调NF-κB信号通路、减少促炎因子IL-1β和IL-8的产生以及抑制细胞死亡。同时研究发现，使用NF-κB信号通路抑制剂BAY11-7082可显著抑制LD的积聚与PEAV的复制。盐酸二甲双胍(metformin hydrochloride)药物同样具有抗PEAV的效力，其可显著抑制LD的积聚、下调NF-κB信号通路、减少促炎因子IL-1β和IL-8的产生以及抑制细胞死亡。总之，我们证明了脂质代谢途径中LD的积聚在 PEAV复制和发病机制中的重要作用，同时探究了metformin hydrochloride通过抑制LD的积聚和炎症应答发挥抗PEAV的作用和减少病理损伤，为PEAV的治疗策略开辟了新的思路。

Abstract:

Coronaviruses are widely transmissible between humans and animals, causing diseases of varying severity. Porcine enteric alphacoronavirus (PEAV) is a newly-discovered pathogenic porcine enteric coronavirus in recent years, which causes watery diarrhea in newborn piglets. The host inflammatory responses to PEAV and its metabolic regulation mechanisms remain unclear, and no antiviral studies have been reported. Therefore, we investigated the pathogenic mechanism and antiviral drugs of PEAV. The transcriptomic analysis of PEAV-infected host cells revealed that PEAV could upregulate lipid metabolism pathways. In lipid metabolism, steady-state energy processes, which can be mediated by lipid droplets (LDs), are the main functions of organelles. LDs are also important in viral infection and inflammation. In infected cells, PEAV increased LD accumulation, upregulated NF-κB signaling, promoted the production of the inflammatory cytokines IL-1β and IL-8, and induced cell death. Inhibiting LD accumulation with a DGAT-1 inhibitor significantly inhibited PEAV replication, downregulated the NF-κB signaling pathway, reduced the production of IL-1β and IL-8, and inhibited cell death. The NF-κB signaling pathway inhibitor BAY11-7082 significantly inhibited LD accumulation and PEAV replication. Metformin hydrochloride also exerted anti-PEAV effects and significantly inhibited LD accumulation, downregulated the NF-κB signaling pathway, reduced the production of IL-1β and IL-8, and inhibited cell death. LD accumulation in the lipid metabolism pathway therefore plays an important role in the replication and pathogenesis of PEAV, and metformin hydrochloride inhibits LD accumulation and the inflammatory response to exert anti-PEAV activity and reducing pathological injury. These findings contribute new targets for developing treatments for PEAV infections.

Key words: Porcine enteric alphacoronavirus , NF-κB inflammatory pathway , lipid droplet , metformin hydrochloride

. 猪肠道α冠状病毒感染增加脂滴的积聚促进病毒复制[J]. Journal of Integrative Agriculture, 2024, 23(3): 988-1005.

Qi Gao, Yongzhi Feng, Ting Gong, Dongdong Wu, Xiaoyu Zheng, Yizhuo Luo, Yunlong Yang, Zebu Song, Lang Gong, Guihong Zhang.

Porcine enteric alphacoronavirus infection increases lipid droplet accumulation to facilitate the virus replication [J]. Journal of Integrative Agriculture, 2024, 23(3): 988-1005.

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猪肠道α冠状病毒感染增加脂滴的积聚促进病毒复制

Porcine enteric alphacoronavirus infection increases lipid droplet accumulation to facilitate the virus replication

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