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In Vitro Antiviral Activity of Hypothiocyanite Against A/H1N1/2009 Pandemic

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In Vitro Antiviral Activity of Hypothiocyanite Against A/H1N1/2009 Pandemic G Model IJHEH-12668; No. of Pages 6 ARTICLE IN PRESS International Journal of Hygiene and Environmental Health xxx (2013) xxx–xxx Contents lists available at SciVerse ScienceDirect International Journal of Hygiene and Environmental Health journa l homepage: www.elsevier.com/locate/ijheh In vitro antiviral activity of hypothiocyanite against A/H1N1/2009 pandemic influenza virus a,b,∗ a a c a a a L. Cegolon , C. Salata , E. Piccoli , V. Juarez , G. Palu’ , G. Mastrangelo , A. Calistri a Padua University, Department of Molecular Medicine, Padua, Italy b Imperial College London, School of Public Health, St. Mary’s Campus, London, UK c Alaxia SAS, Lyon, France a r t i c l e i n f o a b s t r a c t Article history: Influenza virus spreads via small particle aerosols, droplets and fomites, and since it can survive for a short Received 13 December 2012 time on surfaces, can be introduced into the nasal mucosa before it loses infectivity. The hypothiocyanite Received in revised form 28 February 2013 − − ion (OSCN ), product of the lactoperoxidase/H2O2/SCN system of central airways, is emerging as an Accepted 3 March 2013 important molecule for innate defense mechanism against bacteria, fungi and viruses. Here we demon- − strated that OSCN displays virucidal activity in vitro against the A/H1N1 2009 pandemic influenza virus. Keywords: ␮ The concentration required to inhibit viral replication by 50% was 2 M when virus were challenged Influenza prophylaxis − directly with OSCN before cell inoculation. These values were even lower when inoculated cells were Influenza treatment − maintained in contact with enzyme free-OSCN in the culture medium. The last experimental condi- Infection control − Disinfection tions better reflect those of tracheobronchial mucosa, where HOSCN/OSCN is retained in the air–liquid Hypothiocyanite interface and inactivates both the viruses approaching the epithelium from outside and those released − − OSCN lactoperoxidase from the inoculated cells after the replication cycle. Importantly no OSCN cytotoxicity was observed Neuroaminidase in the cellular system employed. The lack of toxicity in humans and the absence of damage on sur- − In vitro faces of fomites suggest a potential use of OSCN to avoid mucosal and environmental transmission of A/H1N1/2009 influenza virus. Since hypothiocyanite is normally present in human airways a low risk of viral resistance is envisaged. In vivo confirmatory studies are needed to evaluate the appropriate dose, regimen and formulation. © 2013 Elsevier GmbH. All rights reserved. Introduction 2007). DUOX employs cytoplasmic nicotinamide adenine dinu- cleotide phosphate (NADPH) as an electron donor to transfer It has been recently shown that the epithelium of central two electrons to oxygen, which is reduced to hydrogen peroxide airways orchestrates an oxidative extracellular microbicidal sys- (H2O2) and then released extracellularly (Grasberger and Refetoff, − tem, consisting of the proteins dual oxidase (DUOX) 1 and 2 2006). LPO catalyzes the oxidation of SCN by H2O2 to yield − secreted by epithelial cells, lactoperoxidase (LPO) secreted by sub- the antimicrobial oxidizing agent hypothiocyanite ion (OSCN ): − − − mucosal glands, and the pseudo-halide thiocyanate anion (SCN ) H2O2 + SCN → H2O + OSCN . − secreted by the epithelia (Moskwa et al., 2007; Conner et al., OSCN is an anion in weak equilibrium with the hypothio- cyanous acid (HOSCN) at neutral pH, where the production of the former predominates. By contrast, at lower pH HOSCN is the major product (Tenovuo et al., 1982). The uncharged nature of HOSCN Abbreviations: ATCC, American tissue culture collection; CO2, carbon diox- enables prompt penetration into the cell wall (Reiter and Perraudin, ide; DNA, deoxyribonucleic acid; DTNB, 5 5 dithio-bis-2-nitrobenzoate; DUOX, dual oxidase; HA, hemagglutinin; HIV, human immunodeficiency virus; HOSCN, hypoth- 1991). Accordingly, the peroxidase system may be considered more iocyanous acid; FBS, fetal bovine serum; RSV, respiratory syncytial virus; LPO, effective at low pH (Tenovuo et al., 1982). The pKa for the couple − lactoperoxidase; MEM, minimal essential medium; MDCK, Madin-Darby Canine OSCN /HOSCN is reportedly being about 4.85 (Nagy et al., 2009). kidney; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; NA, − The reactive blend LPO/H2O2/OSCN at the micromolar concen- neuraminidase; NADPH, nicotinamide adenine dinucleotide phosphate; OD, opti- − tration is reported to be bactericidal against several sensitive Gram cal density; OSCN , hypothiocyanite anion; PBS, phosphate buffered saline; RNA, ribonucleic acid; rRT-PCR, reverse transcriptase real-time polymerase chain reac- positive and negative bacteria, namely Legionella pneumophila, − tion; RSV, respiratory syncytial virus; SCN , thiocyanate; SDS, sequence detection Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa, systems software; TCID, tissue culture infectious dose; TNB, 5-thio-2-nitrobenzoic Listeria monocytogenes, Staphylococcus aureus, Porphyromonas gin- acid; TPCK, l-1-tosylamide-2-phenylethyl chloromethyl ketone. ∗ givalis, and Actinobacillus actinomycetemcomitans (Moskwa et al., Corresponding author at: Padua University, Department of Molecular Medicine, 2007; Conner et al., 2007; Carlsson et al., 1984; Thomas and Aune, Italy. Tel.: +39 3401005331. E-mail addresses: [email protected], [email protected] (L. Cegolon). 1978; Ihalin et al., 1998; Reiter et al., 1976). 1438-4639/$ – see front matter © 2013 Elsevier GmbH. All rights reserved. http://dx.doi.org/10.1016/j.ijheh.2013.03.001 Please cite this article in press as: Cegolon, L., et al., In vitro antiviral activity of hypothiocyanite against A/H1N1/2009 pandemic influenza virus. Int. J. Hyg. Environ. Health (2013), http://dx.doi.org/10.1016/j.ijheh.2013.03.001 G Model IJHEH-12668; No. of Pages 6 ARTICLE IN PRESS 2 L. Cegolon et al. / International Journal of Hygiene and Environmental Health xxx (2013) xxx–xxx Furthermore, fungi as Candida albicans and Candida krusei as Number CRL-2936). Cells were maintained in minimal essential well as viruses like HIV, herpes simplex 1, echovirus (type 11), and medium (MEM, Gibco Life Technologies) containing 10% heat- respiratory syncytial virus (RSV), turned out to be sensitive toward inactivated Fetal Bovine Serum (FBS, Invitrogen Corporation) at ◦ LPO system (Lenander-Lumikari, 1992; Mikola et al., 1995; Pourtois 37 C in a humidified atmosphere with 5% carbon dioxide (CO2). et al., 1990). Although the anti-viral inactivation mechanism of The influenza virus A/California/2009/H1N1 strain was kindly pro- − OSCN is yet unknown, it probably modifies viral surface proteins vided by I. Donatelli (Istituto Superiore di Sanità, Rome, Italy). Virus and prevents the binding or the entry of adenovirus and RSV into was amplified in MDCK cells and the stock was titrated by Tis- − the epithelium. Alternatively, OSCN may inhibit the synthesis or sue Culture Infectious Dose 50 (TCID50) assay, following a protocol assembly of viral nucleic acids and proteins thus preventing the previously described (Klimov et al., 2012). The TCID50 titer was cal- release of virus from infected cells. culated by using the Excel spreadsheet available for download from − Although OSCN has been extensively reported as a product the Yale School of Medicine (www.med.yale.edu/micropath/pdf/ with a broad range of cidal activities, in most cases it was tested as Infectivity%20calculator.xls). − a combination of OSCN and the components of the catalytic reac- tion that ensures a constant production of hypothiocyanite (Björck Reagents − et al., 1975; Barrett and Hawkins, 2011). Enzyme free-OSCN is one of the drug substances of the investigational product ALX- The main chemical reagents employed in this study were: lac- 009 currently developed by Alaxia (Lyon, France), as an inhaled toperoxidase (Alaxia); glucose oxidase (Alaxia); 5 5-dithio-bis-2- therapy for patients with cystic fibrosis. To our best knowledge nitrobenzoate (DTNB) also called Ellman Reagent (Sigma–Aldrich); − enzyme free-OSCN has never been tested against influenza virus sodium thiocyanate (NaSCN, Alaxia SAS) 2 M in physiologi- before. Influenza A is a respiratory virus that causes annual epi- cal saline solution 0.9% (NaCl, Carlo Erba); d-Glucose (Carlo demics and occasional pandemics with an unacceptable number Erba); Tris–HCl (Carlo Erba); sodium borohydride (NaBH4, of deaths and substantial morbidity costs worldwide. Influenza A Sigma–Aldrich); KH2PO4 (Carlo Erba). viruses belong to the Orthomyxoviridae family. Influenza A viruses − are enveloped negative-strand RNA viruses with eight RNA seg- Hypothiocyanite (OSCN ) preparation ments encoding at least 10 viral proteins (Palese, 2007). The virus − particles are enclosed by a lipid envelope, which is derived from For all the experiments, the OSCN solution was freshly pre- − the host cellular membrane. Three viral proteins, the surface glyco- pared in sterilized tubes prior to virus addition. OSCN was proteins hemagglutinin (HA) and neuraminidase (NA) and the M2 produced by LPO catalysis according to Alaxia SAS proprietary tech- − ion channel protein, are embedded in the lipid bilayer of the viral nology. pH of freshly enzyme free-OSCN solutions was adjusted to ◦ envelope. HA and NA are essential during viral replication and are 6.8 with 50 mM KH2PO4, and subsequently stored at 4 C, protected − the major antigenic determinants (Palese, 2007). Influenza viruses from light until use. Due to the high reactivity of OSCN , prepared
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