The natural compound Sanggenon C inhibits PRRSV infection by regulating the TRAF2/NF-κB signalling pathway

Springer Science and Business Media LLC - Tập 54 - Trang 1-16 - 2023
Xiao Liu1, Yanan Zhu1, Dan Wang1, Ran Feng1, Zhihao Chen1, Zifang Zheng2, Yang Li2, Lele Xu1, Haixue Zheng2, Yunpeng Fan1, Yupeng Yin1, Shuqi Xiao1,2
1College of Veterinary Medicine, Northwest A&F University, Yangling, China
2State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou University, Lanzhou, China

Tóm tắt

Porcine reproductive and respiratory syndrome (PRRS) is a serious infectious disease and one of the major causes of death in the global pig industry. PRRS virus (PRRSV) strains have complex and diverse genetic characteristics and cross-protection between strains is low, which complicates vaccine selection; thus, the current vaccination strategy has been greatly compromised. Therefore, it is necessary to identify effective natural compounds for the clinical treatment of PRRS. A small molecule library composed of 720 natural compounds was screened in vitro, and we found that Sanggenon C (SC) was amongst the most effective natural compound inhibitors of PRRSV infection. Compared with ribavirin, SC more significantly inhibited PRRSV infection at both the gene and protein levels and reduced the viral titres and levels of protein expression and inflammatory cytokine secretion to more effectively protect cells from PRRSV infection and damage. Mechanistically, SC inhibits activation of the NF-κB signalling pathway by promoting TRAF2 expression, thereby reducing PRRSV replication. In conclusion, by screening natural compounds, we found that SC suppresses PRRSV infection by regulating the TRAF2/NF-κB signalling pathway. This study contributes to a deeper understanding of the therapeutic targets and pathogenesis of PRRSV infection. More importantly, our results demonstrate that SC has potential as a candidate for the treatment of PRRS.

Tài liệu tham khảo

Kim JH, Kim SC, Kim HJ, Jeong CG, Park GS, Choi JS, Kim WI (2022) Insight into the economic effects of a severe Korean PRRSV1 outbreak in a farrow-to-nursery farm. Animals 12:3024 Yu F, Yan Y, Shi M, Liu HZ, Zhang HL, Yang YB, Huang XY, Gauger PC, Zhang J, Zhang YH, Tong GZ, Tian ZJ, Chen JJ, Cai XH, Liu D, Li G, An TQ (2020) Phylogenetics, genomic recombination, and NSP2 polymorphic patterns of porcine reproductive and respiratory syndrome virus in China and the United States in 2014–2018. J Virol 94:e01813–e01819 Rupasinghe R, Lee K, Liu X, Gauger PC, Zhang J, Martínez-López B (2022) Molecular evolution of porcine reproductive and respiratory syndrome virus field strains from two swine production systems in the Midwestern United States from 2001 to 2020. Microbiol Spectr 10:e0263421 Nathues H, Alarcon P, Rushton J, Jolie R, Fiebig K, Jimenez M, Geurts V, Nathues C (2017) Cost of porcine reproductive and respiratory syndrome virus at individual farm level—an economic disease model. Prev Vet Med 142:16–29 Renken C, Nathues C, Swam H, Fiebig K, Weiss C, Eddicks M, Ritzmann M, Nathues H (2021) Application of an economic calculator to determine the cost of porcine reproductive and respiratory syndrome at farm-level in 21 pig herds in Germany. Porcine Health Manag 7:3 Xia Y, Zhang T, Gong D, Qi J, Jiang S, Yang H, Zhu X, Gan Y, Zhang Y, Han Y, Li Y, Li J (2023) Recombination and mutation in a new HP-PRRSV strain (SD2020) from China. Viruses 15:165 Han G, Xu H, Wang Y, Liu Z, He F (2020) Efficacy evaluation of two commercial vaccines against a recombinant PRRSV2 strain ZJnb16-2 from lineage 8 and 3 in China. Pathogens 9:59 Yang S, Kang I, Cho H, Oh T, Park KH, Min KD, Chae C (2020) A modified-live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine protects late-term pregnancy gilts against a heterologous PRRSV-2 challenge. Can J Vet Res 84:172–180 Weber TE, Schinckel AP, Houseknecht KL, Richert BT (2001) Evaluation of conjugated linoleic acid and dietary antibiotics as growth promotants in weanling pigs. J Anim Sci 79:2542–2549 Chen XJ, Cui QX, Wang GL, Li XL, Zhou XL, Zhao HJ, Zhang MQ, Li MJ, He XJ, Zheng QS, Wang YL, Li D, Hong P (2022) Sanggenon C suppresses tumorigenesis of gastric cancer by blocking ERK-Drp1-mediated mitochondrial fission. J Nat Prod 85:2351–2362 Feng Y, Guo X, Tian H, He Y, Li Y, Jiang X, Zheng H, Xiao S (2022) Induction of HOXA3 by porcine reproductive and respiratory syndrome virus inhibits type I interferon response through negative regulation of HO-1 transcription. J Virol 96:e0186321 Li Z, Ma Z, Dong L, Yang T, Li Y, Jiao D, Han W, Zheng H, Xiao S (2022) Molecular mechanism of porcine epidemic diarrhea virus cell tropism. MBio 13:e0373921 Zheng Z, Fu X, Ling X, Sun H, Li Y, Ma Z, Wei B, Zheng H, Xiao S (2022) Host cells actively resist porcine reproductive and respiratory syndrome virus infection via the IRF8-microRNA-10a-SRP14 regulatory pathway. J Virol 96:e0000322 Karade SS, Franco EJ, Rojas AC, Hanrahan KC, Kolesnikov A, Yu W, MacKerell AD Jr, Hill DC, Weber DJ, Brown AN, Treston AM, Mariuzza RA (2023) Structure-based design of potent iminosugar inhibitors of endoplasmic reticulum α-glucosidase I with anti-SARS-CoV-2 activity. J Med Chem 66:2744–2760 El Aissouq A, Bouachrine M, Bouayyadi L, Ouammou A, Khalil F (2023) Structure-based virtual screening of novel natural products as chalcone derivatives against SARS-CoV-2 M(pro). J Biomol Struct Dyn 8:1–15 Hegazy A, Mahmoud SH, Elshaier Y, Shama NMA, Nasr NF, Ali MA, El-Shazly AM, Mostafa I, Mostafa A (2023) Antiviral activities of plant-derived indole and β-carboline alkaloids against human and avian Influenza viruses. Sci Rep 13:1612 Sow AA, Pahmeier F, Ayotte Y, Anton A, Mazeaud C, Charpentier T, Angelo L, Woo S, Cerikan B, Falzarano D, Abrahamyan L, Lamarre A, Labonté P, Cortese M, Bartenschlager R, LaPlante SR, Chatel-Chaix L (2023) N-Phenylpyridine-3-carboxamide and 6-acetyl-1H-indazole inhibit the RNA replication step of the dengue virus life cycle. Antimicrob Agents Chemother 67:e0133122 Venkatesan A, Dhanabalan AK, Rajendran S, Shanmugasundharam SG, Gunasekaran K, Febin Prabhu Dass J (2022) Structure-based pharmacophore modeling, virtual screening approaches to identifying the potent Hepatitis C viral protease and polymerase novel inhibitors. J Cell Biochem 123:1366–1380 Khatun A, Shabir N, Yoon KJ, Kim WI (2015) Effects of ribavirin on the replication and genetic stability of porcine reproductive and respiratory syndrome virus. BMC Vet Res 11:21 Kim Y, Lee C (2013) Ribavirin efficiently suppresses porcine nidovirus replication. Virus Res 171:44–53 Yan Y, Zhang D, Zhou P, Li B, Huang SY (2017) HDOCK: a web server for protein–protein and protein–DNA/RNA docking based on a hybrid strategy. Nucleic Acids Res 45:W365–W373 Yan Y, Tao H, He J, Huang SY (2020) The HDOCK server for integrated protein–protein docking. Nat Protoc 15:1829–1852 Neumann EJ, Kliebenstein JB, Johnson CD, Mabry JW, Bush EJ, Seitzinger AH, Green AL, Zimmerman JJ (2005) Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States. J Am Vet Med Assoc 227:385–392 Nathues H, Alarcon P, Rushton J, Jolie R, Fiebig K, Jimenez M, Geurts V, Nathues C (2018) Modelling the economic efficiency of using different strategies to control porcine reproductive & respiratory syndrome at herd level. Prev Vet Med 152:89–102 Dat NT, Binh PT, Quynh le TP, Huong HT, Minh CV (2012) Sanggenon C and O inhibit NO production, iNOS expression and NF-κB activation in LPS-induced RAW264.7 cells. Immunopharmacol Immunotoxicol 34:84–88 Li LC, Shen F, Hou Q, Cheng GF (2002) Inhibitory effect and mechanism of action of sanggenon C on human polymorphonuclear leukocyte adhesion to human synovial cells. Acta Pharmacol Sin 23:138–142 Hou XD, Ge GB, Weng ZM, Dai ZR, Leng YH, Ding LL, Jin LL, Yu Y, Cao YF, Hou J (2018) Natural constituents from Cortex Mori Radicis as new pancreatic lipase inhibitors. Bioorg Chem 80:577–584 Li J, Cao X, Chu T, Lin K, Chen L, Lv J, Tan Y, Chen M, Li M, Wang K, Zheng Q, Li D (2023) The circHMGCS1-miR-205-5p-ErBB3 axis mediated the Sanggenon C-induced anti-proliferation effects on human prostate cancer. Pharmacol Res 187:106584 Chen X, Han Y, Chen L, Tian QL, Yin YL, Zhou Q, Zang SZ, Hou J (2022) Discovery and characterization of the flavonoids in Cortex Mori Radicis as naturally occurring inhibitors against intestinal nitroreductases. Chem Biol Interact 368:110222 Bai Y, Chen L, Cao YF, Hou XD, Jia SN, Zhou Q, He YQ, Hou J (2021) Beta-glucuronidase inhibition by constituents of mulberry bark. Planta Med 87:631–641 Chen LD, Liu ZH, Zhang LF, Yao JN, Wang CF (2017) Sanggenon C induces apoptosis of colon cancer cells via inhibition of NO production, iNOS expression and ROS activation of the mitochondrial pathway. Oncol Rep 38:2123–2131 Ma X, Rawnsley DR, Kovacs A, Islam M, Murphy JT, Zhao C, Kumari M, Foroughi L, Liu H, Qi K, Diwan A, Hyrc K, Evans S, Satoh T, French BA, Margulies KB, Javaheri A, Razani B, Mann DL, Mani K, Diwan A (2022) TRAF2, an innate immune sensor, reciprocally regulates mitophagy and inflammation to maintain cardiac myocyte homeostasis. JACC Basic Transl Sci 7:223–243 Jin J, Xiao Y, Hu H, Zou Q, Li Y, Gao Y, Ge W, Cheng X, Sun SC (2015) Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages. Nat Commun 6:5930 Chuang HC, Sheu WH, Lin YT, Tsai CY, Yang CY, Cheng YJ, Huang PY, Li JP, Chiu LL, Wang X, Xie M, Schneider MD, Tan TH (2014) HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance. Nat Commun 5:4602 Schlett JS, Mettang M, Skaf A, Schweizer P, Errerd A, Mulugeta EA, Hein TM, Tsesmelis K, Tsesmelis M, Büttner UFG, Wendt H, Abaei A, Rasche V, Prex V, Nespoli E, Alami NO, Tews D, Walther P, Yilmazer-Hanke D, Oswald F, Dimou L, Wirth T, Baumann B (2023) NF-κB is a critical mediator of post-mitotic senescence in oligodendrocytes and subsequent white matter loss. Mol Neurodegener 18:24 Udawatte DJ, Lang DM, Currier JR, Medin CL, Rothman AL (2022) Dengue virus downregulates TNFR1- and TLR3-stimulated NF-κB activation by targeting RIPK1. Front Cell Infect Microbiol 12:926036 Li X, Song Y, Wang X, Fu C, Zhao F, Zou L, Wu K, Chen W, Li Z, Fan J, Li Y, Li B, Zeng S, Liu X, Zhao M, Yi L, Chen J, Fan S (2023) The regulation of cell homeostasis and antiviral innate immunity by autophagy during classical swine fever virus infection. Emerg Microbes Infect 12:2164217 Huang L, Liu H, Ye G, Liu X, Chen W, Wang Z, Zhao D, Zhang Z, Feng C, Hu L, Yu H, Zhou S, Zhang X, He X, Zheng J, Bu Z, Li J, Weng C (2023) Deletion of African swine fever virus (ASFV) H240R gene attenuates the virulence of ASFV by enhancing NLRP3-mediated inflammatory responses. J Virol 97:e0122722 Chen Y, Song Z, Chang H, Guo Y, Wei Z, Sun Y, Gong L, Zheng Z, Zhang G (2023) Dihydromyricetin inhibits African swine fever virus replication by downregulating toll-like receptor 4-dependent pyroptosis in vitro. Vet Res 54:58 Das R, Mehta DK, Dhanawat M (2022) Medicinal plants in cancer treatment: contribution of nuclear factor-kappa B (NF-kB) inhibitors. Mini Rev Med Chem 22:1938–1962