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Planta Med 2021; 87(07): 538-549
DOI: 10.1055/a-1353-6672
Biological and Pharmacological Activity
Original Papers

Compound Cocktail Inhibits Influenza Viral Pneumonia via Phospholipase Cγ1 Phosphorylation-Related Necroptosis and Partial Autophagy in Natural Killer Cells

Rong Ma  ‡
2   Clinical Research Institute of Integrative Medicine, Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
,
Rui-Qing Ma‡
4   Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
,
Bei Chen
1   Department of Clinical Pharmacy, First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
,
Li-Yu Wang
3   Oncology Department, Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
,
Xiao-Yong Fan
4   Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
› Author AffiliationsSupported by: National Natural Science Foundation of China 81460700
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Correction: Compound Cocktail Inhibits Influenza Viral Pneumonia via Phospholipase Cγ1 Phosphorylation-Related Necroptosis and Partial Autophagy in Natural Killer CellsPlanta Med eFirst
DOI: 10.1055/a-1388-0028

Abstract

Influenza viral infections are prone to global outbreaks and cause pneumonia in affected populations. High morbidity and mortality caused by pneumonia occur during an influenza pandemic. Antivirals or control of inflammation is the primary means of influenza treatment. A compound cocktail composed of arctiin, daidzein, glycyrrhizic acid, and liquiritin inhibited mouse pneumonia resulting from a PR8 viral infection and caused a weight gain after oral administration. Natural killer cell activating receptors, both Ly49D and Ly49H in the lungs, were increased in the treatment in mice. In H3N2 virus-infected natural killer-92MI cells, the cocktail treatment had different effects on phosphorylation sites of phospholipase Cγ1 (PLCγ1) and killed infected cells through necroptosis or late apoptosis, in which RIP3 was increased and both caspase-3 and phosphorylated-JNK in the cells were downregulated. Acid phosphatase activity in viral-infected natural killer-92MI cells was induced by the compound cocktail treatment, which could be related to the p62 decrease in natural killer-92MI cells. In addition, an autophagic flux induction was observed in alveolar basal epithelial cells (A549). Protein p65, but not phosphorylated-p65, was significantly decreased by the treatment. Our results indicate that the compound cocktail strengthened the phosphorylation of PLCγ1-related necroptosis and partial autophagy in natural killer cells, which could yield an inhibitory effect on viral pneumonia in influenza.

Key words

compound cocktail - natural killer cell - PLCγ1 - necroptosis - acid phosphatase - autophagy

Supporting Information

    The effects of the disassembled compound cocktail on inhibition of pneumonia in mice and the immunoblots of phosphorylation of PLCγ1 at sites Tyr1253, Tyr771, and Tyr783 are provided in Supporting Information.

  • Supporting Information


Publication History

Received: 14 July 2020

Accepted after revision: 04 January 2021

Article published online:
05 February 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Bean WJ, Cox NJ, Kendal AP. Recombination of human influenza A viruses in nature. Nature 1980; 5757: 638-640
    CrossrefPubMedGoogle Scholar
  • 2 Hussain M, Galvin HD, Haw TY, Nutsford AN, Husain M. Drug resistance in influenza A virus: the epidemiology and management. Infect Drug Resist 2017; 10: 121-134
    Google Scholar
  • 3 Xu KJ, Song J, Zhao XM. The drug cocktail network. BMC Syst Biol 2012; 6 (Suppl. 01) S5
    PubMedGoogle Scholar
  • 4 Zimmer A, Tendler A, Katzir I, Mayo A, Alon U. Prediction of drug cocktail effects when the number of measurements is limited. PLoS Biol 2017; 15: e2002518
    CrossrefPubMedGoogle Scholar
  • 5 Hung IFN, To KKW, Chan JFW, Cheng VCC, Liu KSH, Tam A, Chan TC, Zhang AJX, Li P, Wong TL, Zhang R, Cheung MKS, Leung W, Lau JYN, Fok M, Chen H, Chan KH, Yuen KY. Efficacy of clarithromycin-naproxen-oseltamivir combination in the treatment of patients hospitalized for influenza A(H3N2) infection: an open-label randomized, controlled, phase IIb/III Trial. Chest 2017; 151: 1069-1080
    CrossrefPubMedGoogle Scholar
  • 6 Sailen B. New treatments for influenza. BMC Med 2012; 10: 104
    CrossrefPubMedGoogle Scholar
  • 7 van Erp EA, van Kampen MR, van Kasteren PB, de Wit J. Viral infection of human natural killer cells. Viruses 2019; 11: 243
    CrossrefPubMedGoogle Scholar
  • 8 Hammer Q, Romagnani C. About training and memory: NK-Cell adaptation to viral infections. Adv Immunol 2017; 133: 171-207
    CrossrefPubMedGoogle Scholar
  • 9 Guo H, Kumar P, Moran TM, Garcia-Sastre A, Zhou Y, Malarkannan S. The functional impairment of natural killer cells during influenza virus infection. Immunol Cell Biol 2009; 87: 579-589
    CrossrefPubMedGoogle Scholar
  • 10 Min-Oo G, Lanier LL. Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection. J Exp Med 2014; 211: 2669-2680
    CrossrefPubMedGoogle Scholar
  • 11 Wang J, Li F, Zheng M, Sun R, Wei H, Tian Z. Lung natural killer cells in mice: phenotype and response to respiratory infection. Immunology 2012; 137: 37-47
    CrossrefPubMedGoogle Scholar
  • 12 Daisuke F, Tadaaki M. Programmed cell death in the pathogenesis of influenza. Int J Mol Sci 2018; 19: 2065
    CrossrefPubMedGoogle Scholar
  • 13 Liu XD, Yang WX, Guan ZZ, Yu WF, Fan B, Xu NZ, Liao DJ. There are only four basic modes of cell death, although there are many ad-hoc variants adapted to different situations. Cell Biosci 2018; 8: 6
    CrossrefPubMedGoogle Scholar
  • 14 Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ 2019; 26: 99-114
    CrossrefPubMedGoogle Scholar
  • 15 Lee KH, Kang TB. The Molecular Links between Cell Death and Inflammasome. Cells 2019; 8: 1057
    CrossrefPubMedGoogle Scholar
  • 16 Lai HC, Chang CJ, Yang CH, Hsu YJ, Chen CC, Lin CS, Tsai YH, Huang TT, Ojcius DM, Tsai YH, Lu CC. Activation of NK cell cytotoxicity by the natural compound 2, 3-butanediol. J Leukoc Biol 2012; 92: 807-814
    CrossrefPubMedGoogle Scholar
  • 17 Chang CJ, Chen YY, Lu CC, Lin CS, Martel J, Tsai SH, Ko YF, Huang TT, Ojcius DM, Young JD, Lai HC. Ganoderma lucidum stimulates NK cell cytotoxicity by inducing NKG2D/NCR activation and secretion of perforin and granulysin. Innate Immun 2014; 20: 301-311
    CrossrefPubMedGoogle Scholar
  • 18 Lu CC, Hsu YJ, Chang CJ, Lin CS, Martel J, Ojcius DM, Ko YF, Lai HC, Young JD. Immunomodulatory properties of medicinal mushrooms: differential effects of water and ethanol extracts on NK cell-mediated cytotoxicity. Innate Immun 2016; 22: 522-533
    CrossrefPubMedGoogle Scholar
  • 19 Lu CC, Chen JK. Resveratrol enhances perforin expression and NK cell cytotoxicity through NKG2D-dependent pathways. J Cell Physiol 2010; 223: 343-351
    PubMedGoogle Scholar
  • 20 Hart AN, Zaske LA, Patterson KM, Drapeau C, Jensen GS. Natural killer cell activation and modulation of chemokine receptor profile in vitro by an extract from the cyanophyta Aphanizomenon flos-aquae . J Med Food 2007; 10: 435-441
    CrossrefPubMedGoogle Scholar
  • 21 Ma R, Zhang LX, Chen B, Tian XC, Zhu L, Ma L, Yu J, Cui FJ. Pharmaceutical composition and its use in preparing medicine for treating pneumonia or/and enhancing natural killer cell activity in upper respiratory tract infection. Chinese Patent CN106943416B, 2020
    Google Scholar
  • 22 Borhani K, Bamdad T, Hashempour T. Low dose of lenalidomide enhances NK cell activity: possible implication as an adjuvant. Iran J Immunol 2017; 14: 151-158
    PubMedGoogle Scholar
  • 23 Kowalski S, Hać S, Wyrzykowski D, Zauszkiewicz-Pawlak A, Inkielewicz-Stępniak I. Selective cytotoxicity of vanadium complexes on human pancreatic ductal adenocarcinoma cell line by inducing necroptosis, apoptosis and mitotic catastrophe process. Oncotarget 2017; 36: 60324-60341
    CrossrefPubMedGoogle Scholar
  • 24 Fujikura D, Miyazaki T. Programmed cell death in the pathogenesis of influenza. Int J Mol Sci 2018; 19: 2065
    CrossrefPubMedGoogle Scholar
  • 25 Bleasdale JE, Fisher SK. Use of U-73122 as an inhibitor of phospholipase c-dependent processes. Neuroprotocols 1993; 3: 125-133
    CrossrefPubMedGoogle Scholar
  • 26 Henneberry MO, Engel G, Grayhack JT. Acid phosphatase. Urol Clin North Am 1979; 6: 629-641
    CrossrefPubMedGoogle Scholar
  • 27 Guo H, Kumar P, Moran TM, Garcia-Sastre A, Zhou Y, Malarkannan S. The functional impairment of natural killer cells during influenza virus infection. Immunol Cell Biol 2009; 87: 579-589
    CrossrefPubMedGoogle Scholar
  • 28 Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8⁺ T cells. Nat Rev Immunol 2011; 11: 645-657
    CrossrefPubMedGoogle Scholar
  • 29 Zhu L, Ly H, Liang Y. PLC-γ1 signaling plays a subtype-specific role in post binding cell entry of influenza A virus. J Virol 2014; 88: 417-424
    CrossrefPubMedGoogle Scholar
  • 30 Zhu L, Yuan C, Ding X, Xu S, Yang J, Liang Y, Zhu QY. PLC-γ1 is involved in the inflammatory response induced by influenza A virus H1N1 infection. Virology 2016; 496: 131-137
    CrossrefPubMedGoogle Scholar
  • 31 Ma R, Deng JY, Liu DH, Cui XL, Bi MG. The effects of Yinqiao detoxifcation oral liquid on seurm concentration of TNF-α and TGF-β1 in SCID mouse infected by influenza virus FM1. Zhongguo Zhong Yao Za Zhi 2010; 35: 2488-2490
    PubMedGoogle Scholar
  • 32 Abea K, Yanoa T, Tanno M, Miki T, Kuno A, Sato T, Kouzu H, Nakata K, Ohwada W, Kimura Y, Sugawara H, Shibata S, Igaki Y, Ino S, Miura T. mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation. Biochim Biophys Acta Mol Basis Dis 2019; 1865: 165552
    CrossrefPubMedGoogle Scholar
  • 33 Kesavardhana S, Kuriakose T, Guy CS, Samir P, Malireddi RKS, Mishra A, Kanneganti TD. ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed cell death. J Exp Med 2017; 214: 2217-2229
    CrossrefPubMedGoogle Scholar
  • 34 Wurzer WJ, Planz O, Ehrhardt C, Giner M, Silberzahn T, Pleschka S, Ludwig S. Caspase 3 activation is essential for efficient influenza virus propagation. EMBO J 2003; 22: 2717-2728
    CrossrefPubMedGoogle Scholar
  • 35 Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 2005; 120: 649-661
    CrossrefPubMedGoogle Scholar
  • 36 Baginska J. Study of the involvement of autophagy in the acquisition of tumor resistance to Natural Killer-mediated lysis. Cancer Université Paris Sud-Paris XI; 2013: 37. Accessed June 27, 2017 at: https://tel.archives-ouvertes.fr/tel-01236940/document
    Google Scholar
  • 37 Kesarwani P, Chakraborty P, Gudi R, Chatterjee S, Scurti G, Toth K, Simms P, Husain M, Armeson K, Husain S, Garrett-Mayer E, Vasu C, Nishimura MI, Mehrotra S. Blocking TCR restimulation induced necroptosis in adoptively transferred T cells improves tumor control. Oncotarget 2016; 7: 69371-69383
    CrossrefPubMedGoogle Scholar
  • 38 Nacken W, Anhlan D, Hrincius ER, Mostafa A, Wolff T, Sadewasser A, Pleschka S, Ehrhardt C, Ludwig S. Activation of c-jun N-terminal kinase upon influenza A virus (IAV) infection is independent of pathogen-related receptors but dependent on amino acid sequence variations of IAV NS1. J Virol 2014; 88: 8843-8852
    CrossrefPubMedGoogle Scholar
  • 39 Lee J, Kim J, Son K, dʼAlexandry dʼOrengiani AP, Min JY. Acid phosphatase 2 (ACP2) is required for membrane fusion during influenza virus entry. Sci Rep 2017; 7: 43893
    CrossrefPubMedGoogle Scholar
  • 40 Zhang XJ, Chen S, Huang KX, Le WD. Why should autophagic flux be assessed?. Acta Pharmacol Sin 2013; 34: 595-599
    CrossrefPubMedGoogle Scholar
  • 41 Castillo K, Valenzuela V, Matus S, Nassif M, Oñate M, Fuentealba Y, Encina G, Irrazabal T, Parsons G, Court FA, Schneider BL, Armentano D, Hetz C. Measurement of autophagy flux in the nervous system in vivo . Cell Death Dis 2013; 4: e917
    CrossrefPubMedGoogle Scholar
  • 42 Sakuma K, Kinoshita M, Ito Y, Aizawa M, Aoi W, Yamaguchi A. p62/SQSTM1 but not LC3 is accumulated in sarcopenic muscle of mice. J Cachexia Sarcopenia Muscle 2016; 7: 204-212
    CrossrefPubMedGoogle Scholar