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Medical Microbiology and Immunology
Published in: Medical Microbiology and Immunology 2/2011

01-05-2011 | Original Investigation

Therapy of experimental influenza virus infection with pyrrolidine dithiocarbamate

Authors: Nadine Wiesener, Christin Zimmer, Nadine Jarasch-Althof, Peter Wutzler, Andreas Henke

Published in: Medical Microbiology and Immunology | Issue 2/2011

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Abstract

The search for new antiviral strategies to treat influenza A virus (IAV) infections is one major international health care activity. Hereby, the IAV-caused misuse of cellular nuclear factor kappa B (NF-κB) signaling pathways in infected cells represents one target for antiviral therapy. In the present study, pyrrolidine dithiocarbamate (PDTC), which is known as an antioxidant and as an inhibitor of IAV-induced NF-κB activation, was studied in vivo. After the antiviral activity of PDTC was confirmed in MDCK cells, mice—infected with the mouse-adapted strain of IAV A/PR/8/34 (H1N1)—were treated intraperitoneally simultaneously with PDTC (75, 150, 200 mg/kg body weight). The influence of PDTC administrations was evaluated on viral replication and inflammatory reactions in lung tissue up to 14 days postinfection (p. i.). This therapy increased survival up to 80% and reduced IAV-caused weight loss and viral replication in lung tissue in a dose-dependent manner. Protective effects were less pronounced, if the therapy started later on during an ongoing IAV infection. In addition, simultaneous PDTC treatment also limited IAV-caused infiltration of immune cells as well as local interferon-γ expression in lung tissue. These results imply that PDTC decreases IAV-caused disease in mice significantly. Therefore, the development of drugs like PDTC that interfere with NF-κB signaling may represent a modern focus of anti-IAV therapy.
Literature
1.
Taubenberger JK, Kash JC (2010) Influenza virus evolution, host adaptation, and pandemic formation. Cell Host Microbe 7(6):440–451PubMedCrossRef
2.
Taubenberger JK, Morens DM (2010) Influenza: the once and future pandemic. Public Health Rep 125(Suppl 3):16–26PubMed
3.
Krug RM, Aramini JM (2009) Emerging antiviral targets for influenza A virus. Trends Pharmacol Sci 30(6):269–277PubMedCrossRef
4.
Lin C, Zimmer SG, Lu Z, Holland RE Jr, Dong Q, Chambers TM (2001) The involvement of a stress-activated pathway in equine influenza virus-mediated apoptosis. Virology 287(1):202–213PubMedCrossRef
5.
Morris SJ, Price GE, Barnett JM, Hiscox SA, Smith H, Sweet C (1999) Role of neuraminidase in influenza virus-induced apoptosis. J Gen Virol 80:137–146PubMed
6.
Takizawa T, Matsukawa S, Higuchi Y, Nakamura S, Nakanishi Y, Fukuda R (1993) Induction of programmed cell death (apoptosis) by influenza virus infection in tissue culture cells. J Gen Virol 74:2347–2355PubMedCrossRef
7.
Uchide N, Ohyama K, Bessho T, Yuan B, Yamakawa T (2002) Effect of antioxidants on apoptosis induced by influenza virus infection: inhibition of viral gene replication and transcription with pyrrolidine dithiocarbamate. Antiviral Res 56(3):207–217PubMedCrossRef
8.
Miyamoto D, Kusagaya Y, Endo N, Sometani A, Takeo S, Suzuki T, Arima Y, Nakajima K, Suzuki Y (1998) Thujaplicin-copper chelates inhibit replication of human influenza viruses. Antiviral Res 39(2):89–100PubMedCrossRef
9.
Uchide N, Ohyama K, Bessho T, Yuan B, Yamakawa T (2002) Apoptosis in cultured human fetal membrane cells infected with influenza virus. Biol Pharm Bull 25(1):109–114PubMedCrossRef
10.
Shi XL, Shi ZH, Huang H, Zhu HG, Zhou P, Ju D (2010) Therapeutic effect of recombinant human catalase on H1N1 influenza-induced pneumonia in mice. Inflammation 33(3):166–172PubMedCrossRef
11.
Knobil K, Choi AM, Weigand GW, Jacoby DB (1998) Role of oxidants in influenza virus-induced gene expression. Am J Physiol 274:134–142
12.
Lowy RJ, Dimitrov DS (1997) Characterization of influenza virus-induced death of J774.1 macrophages. Exp Cell Res 234(2):249–258PubMedCrossRef
13.
Olsen CW, Dybdahl-Sissoko N, Hinshaw VS (1996) The influence of calcium and reactive oxygen species on influenza virus-induced apoptosis. Cell Death Differ 3(2):191–197PubMed
14.
Meyer M, Schreck R, Baeuerle PA (1993) H2O2 and antioxidants have opposite effects on activation of NF-kappa B and AP-1 in intact cells: AP-1 as secondary antioxidant-responsive factor. EMBO J 12(5):2005–2015PubMed
15.
Schreck R, Meier B, Mannel DN, Droge W, Baeuerle PA (1992) Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med 175(5):1181–1194PubMedCrossRef
16.
Hayakawa M, Miyashita H, Sakamoto I, Kitagawa M, Tanaka H, Yasuda H, Karin M, Kikugawa K (2003) Evidence that reactive oxygen species do not mediate NF-kappa B activation. EMBO J 22(13):3356–3366PubMedCrossRef
17.
Kim I, Kim CH, Kim JH, Lee J, Choi JJ, Chen ZA, Lee MG, Chung KC, Hsu CY, Ahn YS (2004) Pyrrolidine dithiocarbamate and zinc inhibit proteasome-dependent proteolysis. Exp Cell Res 298(1):229–238PubMedCrossRef
18.
Borrello S, Demple B (1997) NF kappa B-independent transcriptional induction of the human manganous superoxide dismutase gene. Arch Biochem Biophys 348(2):289–294PubMedCrossRef
19.
Hartsfield CL, Alam J, Choi AM (1998) Transcriptional regulation of the heme oxygenase 1 gene by pyrrolidine dithiocarbamate. FASEB J 12(15):1675–1682PubMed
20.
Wild AC, Mulcahy RT (1999) Pyrrolidine dithiocarbamate up-regulates the expression of the genes encoding the catalytic and regulatory subunits of gamma-glutamylcysteine synthetase and increases intracellular glutathione levels. Biochem J 338:659–665PubMedCrossRef
21.
Uchide N, Ohyama K, Bessho T, Toyoda H (2005) Inhibition of influenza-virus-induced apoptosis in chorion cells of human fetal membranes by nordihydroguaiaretic Acid. Intervirology 48(5):336–340PubMedCrossRef
22.
Uchide N, Ohyama K (2003) Antiviral function of pyrrolidine dithiocarbamate against influenza virus: the inhibition of viral gene replication and transcription. J Antimicrob Chemother 52(1):8–10PubMedCrossRef
23.
Flory E, Kunz M, Scheller C, Jassoy C, Stauber R, Rapp UR, Ludwig S (2000) Influenza virus-induced NF-kappa B-dependent gene expression is mediated by overexpression of viral proteins and involves oxidative radicals and activation of Ikappa B kinase. J Biol Chem 275(12):8307–8314PubMedCrossRef
24.
Nimmerjahn F, Dudziak D, Dirmeier U, Hobom G, Riedel A, Schlee M, Staudt LM, Rosenwald A, Behrends U, Bornkamm GW, Mautner J (2004) Active NF-kappa B signalling is a prerequisite for influenza virus infection. J Gen Virol 85:2347–2356PubMedCrossRef
25.
Wurzer WJ, Ehrhardt C, Pleschka S, Berberich-Siebelt F, Wolff T, Walczak H, Planz O, Ludwig S (2004) NF-kappa B-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas/FasL is crucial for efficient influenza virus propagation. J Biol Chem 279(30):30931–30937PubMedCrossRef
26.
Schmolke M, Viemann D, Roth J, Ludwig S (2009) Essential impact of NF-kappaB signaling on the H5N1 influenza A virus-induced transcriptome. J Immunol 183(8):5180–5189PubMedCrossRef
27.
Wei L, Sandbulte MR, Thomas PG, Webby RJ, Homayouni R, Pfeffer LM (2006) NFkappa B negatively regulates interferon-induced gene expression and anti-influenza activity. J Biol Chem 281(17):11678–11684PubMedCrossRef
28.
Uchide N, Toyoda H (2008) Future target molecules for influenza treatment. Mini Rev Med Chem 8(5):491–495PubMedCrossRef
29.
Chabicovsky M, Prieschl-Grassauer E, Seipelt J, Muster T, Szolar OH, Hebar A, Doblhoff-Dier O (2010) Pre-clinical safety evaluation of pyrrolidine dithiocarbamate. Basic Clin Pharmacol Toxicol 107(3):758–767PubMedCrossRef
30.
Reed LJ, Muench H (1938) A simple method of estimating fifty percent endpoints. Am J Hyg 27:493–497
31.
Chieux V, Chehadeh W, Harvey J, Haller O, Wattre P, Hober D (2001) Inhibition of coxsackievirus B4 replication in stably transfected cells expressing human MxA protein. Virology 283(1):84–92PubMedCrossRef
32.
Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate- phenol-chloroform extraction. Anal Biochem 162(1):156–159PubMedCrossRef
33.
Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9):e45PubMedCrossRef
34.
Henke A, Launhardt H, Klement K, Stelzner A, Zell R, Munder T (2000) Apoptosis in coxsackievirus B3-caused diseases: interaction between the capsid protein VP2 and the proapoptotic protein siva. J Virol 74(9):4284–4290PubMedCrossRef
35.
Kim CH, Kim JH, Hsu CY, Ahn YS (1999) Zinc is required in pyrrolidine dithiocarbamate inhibition of NF-kappa B activation. FEBS Lett 449(1):28–32PubMedCrossRef
36.
Ulmer JB, Deck RR, DeWitt CM, Friedman A, Donnelly JJ, Liu MA (1994) Protective immunity by intramuscular injection of low doses of influenza virus DNA vaccines. Vaccine 12(16):1541–1544PubMedCrossRef
37.
Henke A (2002) DNA immunization—a new chance in vaccine research? Med Microbiol Immunol 191(3–4):187–190PubMed
38.
Schmidt RE (2002) Drug under test: influenza—Relenza in daily practice. Experience during the influenza season 1999/2000. Med Microbiol Immunol 191(3–4):175–179PubMed
39.
Harrod ME, Emery S, Dwyer DE (2006) Antivirals in the management of an influenza pandemic. Med J Aust 185(Suppl 10):S58–S61PubMed
40.
Monto AS, McKimm-Breschkin JL, Macken C, Hampson AW, Hay A, Klimov A, Tashiro M, Webster RG, Aymard M, Hayden FG, Zambon M (2006) Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother 50(7):2395–2402PubMedCrossRef
41.
Sheu TG, Deyde VM, Okomo-Adhiambo M, Garten RJ, Xu X, Bright RA, Butler EN, Wallis TR, Klimov AI, Gubareva LV (2008) Surveillance for neuraminidase inhibitor resistance among human influenza A, B viruses circulating worldwide from 2004 to 2008. Antimicrob Agents Chemother 52(9):3284–3292PubMedCrossRef
42.
Mazur I, Wurzer WJ, Ehrhardt C, Pleschka S, Puthavathana P, Silberzahn T, Wolff T, Planz O, Ludwig S (2007) Acetylsalicylic acid (ASA) blocks influenza virus propagation via its NF-kappa B-inhibiting activity. Cell Microbiol 9(7):1683–1694PubMedCrossRef
43.
Gaudernak E, Seipelt J, Triendl A, Grassauer A, Kuechler E (2002) Antiviral effects of pyrrolidine dithiocarbamate on human rhinoviruses. J Virol 76(12):6004–6015PubMedCrossRef
44.
Kang MS, Choi EK, Choi DH, Ryu SY, Lee HH, Kang HC, Koh JT, Kim OS, Hwang YC, Yoon SJ, Kim SM, Yang KH, Kang IC (2008) Antibacterial activity of pyrrolidine dithiocarbamate. FEMS Microbiol Lett 280(2):250–254PubMedCrossRef
45.
Krenn BM, Holzer B, Gaudernak E, Triendl A, van Kuppeveld FJ, Seipelt J (2005) Inhibition of polyprotein processing and RNA replication of human rhinovirus by pyrrolidine dithiocarbamate involves metal ions. J Virol 79(22):13892–13899PubMedCrossRef
46.
Lanke K, Krenn BM, Melchers WJ, Seipelt J, van Kuppeveld FJ (2007) PDTC inhibits picornavirus polyprotein processing and RNA replication by transporting zinc ions into cells. J Gen Virol 88(Pt 4):1206–1217PubMedCrossRef
47.
Wurzer WJ, Planz O, Ehrhardt C, Giner M, Silberzahn T, Pleschka S, Ludwig S (2003) Caspase 3 activation is essential for efficient influenza virus propagation. EMBO J 22(11):2717–2728PubMedCrossRef
48.
Erl W, Weber C, Hansson GK (2000) Pyrrolidine dithiocarbamate-induced apoptosis depends on cell type, density, and the presence of Cu2+ and Zn2+. Am J Physiol Cell Physiol 278(6):C1116–C1125PubMed
49.
Zabel U, Schreck R, Baeuerle PA (1991) DNA binding of purified transcription factor NF-kappa B. Affinity, specificity, Zn2+ dependence, and differential half-site recognition. J Biol Chem 266(1):252–260PubMed
50.
Shumilla JA, Wetterhahn KE, Barchowsky A (1998) Inhibition of NF-kappa B binding to DNA by chromium, cadmium, mercury, zinc, and arsenite in vitro: evidence of a thiol mechanism. Arch Biochem Biophys 349(2):356–362PubMedCrossRef
51.
Oxford JS, Perrin DD (1974) Inhibition of the particle-associated RNA-dependent RNA polymerase activity of influenza viruses by chelating agents. J Gen Virol 23(1):59–71PubMedCrossRef
52.
Michaelis M, Geiler J, Naczk P, Sithisarn P, Ogbomo H, Altenbrandt B, Leutz A, Doerr HW, Cinatl J Jr (2010) Glycyrrhizin inhibits highly pathogenic H5N1 influenza A virus-induced pro-inflammatory cytokine and chemokine expression in human macrophages. Med Microbiol Immunol 199:291–297PubMedCrossRef
53.
Geiler J, Michaelis M, Sithisarn P, Cinatl J Jr (2010) Comparison of pro-inflammatory cytokine expression and cellular signal transduction in human macrophages infected with different influenza A viruses. Med Microbiol Immunol. doi:10.​1007/​s00430-010-0173-y
54.
Julkunen I, Sareneva T, Pirhonen J, Ronni T, Melen K, Matikainen S (2001) Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression. Cytokine Growth Factor Rev 12(2–3):171–180PubMedCrossRef
55.
Geiler J, Michaelis M, Naczk P, Leutz A, Langer K, Doerr HW, Cinatl J Jr (2009) N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus. Biochem Pharmacol 79(3):413–420PubMedCrossRef
56.
Cheung CY, Poon LL, Lau AS, Luk W, Lau YL, Shortridge KF, Gordon S, Guan Y, Peiris JS (2002) Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360(9348):1831–1837PubMedCrossRef
57.
Starko KM (2009) Salicylates and pandemic influenza mortality, 1918–1919 pharmacology, pathology, and historic evidence. Clin Infect Dis 49(9):1405–1410PubMedCrossRef
58.
Eyers S, Weatherall M, Shirtcliffe P, Perrin K, Beasley R (2010) The effect on mortality of antipyretics in the treatment of influenza infection: systematic review and meta-analysis. J R Soc Med 103(10):403–411PubMedCrossRef
Metadata
Title
Therapy of experimental influenza virus infection with pyrrolidine dithiocarbamate
Authors
Nadine Wiesener
Christin Zimmer
Nadine Jarasch-Althof
Peter Wutzler
Andreas Henke
Publication date
01-05-2011
Publisher
Springer-Verlag
Published in
Medical Microbiology and Immunology / Issue 2/2011
Print ISSN: 0300-8584
Electronic ISSN: 1432-1831
DOI
https://doi.org/10.1007/s00430-010-0182-x

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