1887

Abstract

Some free fatty acids derived from milk and vegetable oils are known to have potent antiviral and antibacterial properties. However, therapeutic applications of short- to medium-chain fatty acids are limited by physical characteristics such as immiscibility in aqueous solutions. We evaluated a novel proprietary formulation based on an emulsion of short-chain caprylic acid, ViroSAL, for its ability to inhibit a range of viral infections and ViroSAL inhibited the enveloped viruses Epstein–Barr, measles, herpes simplex, Zika and orf parapoxvirus, together with Ebola, Lassa, vesicular stomatitis and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) pseudoviruses, in a concentration- and time-dependent manner. Evaluation of the components of ViroSAL revealed that caprylic acid was the main antiviral component; however, the ViroSAL formulation significantly inhibited viral entry compared with caprylic acid alone. , ViroSAL significantly inhibited Zika and Semliki Forest virus replication in mice following the inoculation of these viruses into mosquito bite sites. In agreement with studies investigating other free fatty acids, ViroSAL had no effect on norovirus, a non-enveloped virus, indicating that its mechanism of action may be surfactant disruption of the viral envelope. We have identified a novel antiviral formulation that is of great interest for the prevention and/or treatment of a broad range of enveloped viruses, particularly those of the skin and mucosal surfaces.

Funding
This study was supported by the:
  • Dalan Bailey , Medical Research Council , (Award MR/P021735/1)
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001472
2020-07-21
2020-10-23
Loading full text...

Full text loading...

/deliver/fulltext/jgv/10.1099/jgv.0.001472/jgv001472.html?itemId=/content/journal/jgv/10.1099/jgv.0.001472&mimeType=html&fmt=ahah

References

  1. Thormar H, Hilmarsson H. The role of microbicidal lipids in host defense against pathogens and their potential as therapeutic agents. Chem Phys Lipids 2007; 150:1–11 [CrossRef]
    [Google Scholar]
  2. Churchward CP, Alany RG, Snyder LAS. Alternative antimicrobials: the properties of fatty acids and monoglycerides. Crit Rev Microbiol 2018; 44:561–570 [CrossRef]
    [Google Scholar]
  3. Thormar H, Isaacs CE, Brown HR, Barshatzky MR, Pessolano T. Inactivation of enveloped viruses and killing of cells by fatty acids and monoglycerides. Antimicrob Agents Chemother 1987; 31:27–31 [CrossRef]
    [Google Scholar]
  4. Hilmarsson H, Kristmundsdottir T, Thormar H. Virucidal activities of medium- and long-chain fatty alcohols, fatty acids and monoglycerides against herpes simplex virus types 1 and 2: comparison at different pH levels. APMIS 2005; 113:58–65 [CrossRef]
    [Google Scholar]
  5. Dichtelmüller H, Rudnick D, Kloft M. Inactivation of lipid enveloped viruses by octanoic acid treatment of immunoglobulin solution. Biologicals 2002; 30:135–142 [CrossRef]
    [Google Scholar]
  6. Pingen M, Bryden SR, Pondeville E, Schnettler E, Kohl A et al. Host inflammatory response to mosquito bites enhances the severity of arbovirus infection. Immunity 2016; 44:1455–1469 [CrossRef]
    [Google Scholar]
  7. Isaacs CE, Kashyap S, Heird WC, Thormar H. Antiviral and antibacterial lipids in human milk and infant formula feeds. Arch Dis Child 1990; 65:861–864 [CrossRef]
    [Google Scholar]
  8. Kohn A, Gitelman J, Inbar M. Unsaturated free fatty acids inactivate animal enveloped viruses. Arch Virol 1980; 66:301–307 [CrossRef]
    [Google Scholar]
  9. Feederle R, Neuhierl B, Bannert H, Geletneky K, Shannon-Lowe C et al. Epstein-Barr virus B95.8 produced in 293 cells shows marked tropism for differentiated primary epithelial cells and reveals interindividual variation in susceptibility to viral infection. Int. J. Cancer 2007; 121:588–594 [CrossRef]
    [Google Scholar]
  10. Scagliarini A, McInnes CJ, Gallina L, Dal Pozzo F, Scagliarini L et al. Antiviral activity of HPMPC (cidofovir) against ORF virus infected lambs. Antiviral Res 2007; 73:169–174 [CrossRef]
    [Google Scholar]
  11. Minson AC, Hodgman TC, Digard P, Hancock DC, Bell SE et al. An analysis of the biological properties of monoclonal antibodies against glycoprotein D of herpes simplex virus and identification of amino acid substitutions that confer resistance to neutralization. Journal of General Virology 1986; 67:1001–1013 [CrossRef]
    [Google Scholar]
  12. Fletcher NF, Humphreys E, Jennings E, Osburn W, Lissauer S et al. Hepatitis C virus infection of cholangiocarcinoma cell lines. J Gen Virol 2015; 96:1380–1388 [CrossRef]
    [Google Scholar]
  13. Broer R, Boson B, Spaan W, Cosset François-Loïc, Corver J. Important role for the transmembrane domain of severe acute respiratory syndrome coronavirus spike protein during entry. J Virol 2006; 80:1302–1310 [CrossRef]
    [Google Scholar]
  14. Hashimoto K, Ono N, Tatsuo H, Minagawa H, Takeda M et al. SLAM (CD150)-independent measles virus entry as revealed by recombinant virus expressing green fluorescent protein. J Virol 2002; 76:6743–6749 [CrossRef]
    [Google Scholar]
  15. Reed LJ MH. A simple method of estimating fifty per cent endpoints. Am J Hygiene 1938; 27:493–497
    [Google Scholar]
  16. Delecluse H-J, Hilsendegen T, Pich D, Zeidler R, Hammerschmidt W. Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells. Proc Natl Acad Sci U S A 1998; 95:8245–8250 [CrossRef]
    [Google Scholar]
  17. Shannon-Lowe CD, Neuhierl B, Baldwin G, Rickinson AB, Delecluse H-J. Resting B cells as a transfer vehicle for Epstein-Barr virus infection of epithelial cells. Proc Natl Acad Sci U S A 2006; 103:7065–7070 [CrossRef]
    [Google Scholar]
  18. Shannon-Lowe C, Adland E, Bell AI, Delecluse H-J, Rickinson AB et al. Features distinguishing Epstein-Barr virus infections of epithelial cells and B cells: viral genome expression, genome maintenance, and genome amplification. J Virol 2009; 83:7749–7760 [CrossRef]
    [Google Scholar]
  19. Ren Y, Bell S, Zenner HL, Lau S-YK, Crump CM. Glycoprotein M is important for the efficient incorporation of glycoprotein H–L into herpes simplex virus type 1 particles. J Gen Virol 2012; 93:319–329 [CrossRef]
    [Google Scholar]
  20. Chavali PL, Stojic L, Meredith LW, Joseph N, Nahorski MS et al. Neurodevelopmental protein Musashi-1 interacts with the Zika genome and promotes viral replication. Science 2017; 357:83–88 [CrossRef]
    [Google Scholar]
  21. McInnes CJ, Wood AR, Nettleton PF, Gilray JA. Genomic comparison of an avirulent strain of ORF virus with that of a virulent wild type isolate reveals that the ORF virus G2L gene is non-essential for replication. Virus Genes 2001; 22:141–150 [CrossRef]
    [Google Scholar]
  22. Wobus CE, Karst SM, Thackray LB, Chang K-O, Sosnovtsev SV et al. Replication of norovirus in cell culture reveals a tropism for dendritic cells and macrophages. PLoS Biol 2004; 2:e432 [CrossRef]
    [Google Scholar]
  23. Ülper L, Sarand I, Rausalu K, Merits A. Construction, properties, and potential application of infectious plasmids containing Semliki Forest virus full-length cDNA with an inserted intron. J Virol Methods 2008; 148:265–270 [CrossRef]
    [Google Scholar]
  24. Ferguson MC, Saul S, Fragkoudis R, Weisheit S, Cox J et al. Ability of the encephalitic arbovirus Semliki Forest virus to cross the blood-brain barrier is determined by the charge of the E2 glycoprotein. J Virol 2015; 89:7536–7549 [CrossRef]
    [Google Scholar]
  25. Moser LA, Boylan BT, Moreira FR, Myers LJ, Svenson EL et al. Growth and adaptation of Zika virus in mammalian and mosquito cells. PLoS Negl Trop Dis 2018; 12:e0006880 [CrossRef]
    [Google Scholar]
  26. Laverty G, Gilmore BF, Jones DS, Coyle L, Folan M et al. Antimicrobial efficacy of an innovative emulsion of medium chain triglycerides against canine and feline periodontopathogens. J Small Anim Pract 2015; 56:253–263 [CrossRef]
    [Google Scholar]
  27. Bryden SR, Pingen M, Lefteri DA, Miltenburg J, Delang L et al. Pan-viral protection against arboviruses by activating skin macrophages at the inoculation site. Sci Transl Med 2020; 12:eaax2421 [CrossRef]
    [Google Scholar]
  28. Li Q, Liu Q, Huang W, Li X, Wang Y. Current status on the development of pseudoviruses for enveloped viruses. Rev Med Virol 2018; 28:e1963 [CrossRef][PubMed]
    [Google Scholar]
  29. Ruigrok RWH, Hewat EA, Wade RH. Low pH deforms the influenza virus envelope. J Virol 1992; 73:995–998 [CrossRef]
    [Google Scholar]
  30. Hogan S, Zapotoczna M, Stevens NT, Humphreys H, O'Gara JP et al. Eradication of Staphylococcus aureus catheter-related biofilm infections using ML:8 and Citrox. Antimicrob Agents Chemother 2016; 60:5968–5975 [CrossRef]
    [Google Scholar]
  31. McDermott FD, Folan DMA, Winter DC, Folan MA, Baird AW. Gnotobiotic Human Colon Ex Vivo. Gastroenterol Res 2015; 8:247–252 [CrossRef]
    [Google Scholar]
  32. Jackman J, Yoon B, Cho N-J, Cho N-J. Nanotechnology formulations for antibacterial free fatty acids and monoglycerides. Molecules 2016; 21:305 [CrossRef]
    [Google Scholar]
  33. Yoon B, Jackman J, Valle-González E, Cho N-J. Antibacterial free fatty acids and monoglycerides: biological activities, experimental testing, and therapeutic applications. Int J Mol Sci 2018; 19:1114 [CrossRef]
    [Google Scholar]
  34. Buranasuksombat U, Kwon YJ, Turner M, Bhandari B. Influence of emulsion droplet size on antimicrobial properties. Food Sci Biotechnol 2011; 20:793–800 [CrossRef]
    [Google Scholar]
  35. Ma Q, Davidson PM, Zhong Q. Antimicrobial properties of microemulsions formulated with essential oils, soybean oil, and Tween 80. Int J Food Microbiol 2016; 226:20–25 [CrossRef][PubMed]
    [Google Scholar]
  36. Donsì F, Ferrari G. Essential oil nanoemulsions as antimicrobial agents in food. J Biotechnol 2016; 233:106–120 [CrossRef]
    [Google Scholar]
  37. Thormar H, Isaacs CE, Kim KS, Brown HR. Inactivation of visna virus and other enveloped viruses by free fatty acids and monoglycerides. Ann N Y Acad Sci 1994; 724:465–471 [CrossRef]
    [Google Scholar]
  38. Yoon BK, Jackman JA, Kim MC, Cho N-J. Spectrum of membrane morphological responses to antibacterial fatty acids and related surfactants. Langmuir 2015; 31:10223–10232 [CrossRef]
    [Google Scholar]
  39. Yoon BK, Jackman JA, Kim MC, Sut TN, Cho N-J. Correlating membrane morphological responses with micellar aggregation behavior of Capric acid and Monocaprin. Langmuir 2017; 33:2750–2759 [CrossRef]
    [Google Scholar]
  40. Lundblad JL, Seng RL. Inactivation of Lipid-Enveloped viruses in proteins by caprylate. Vox Sang 1991; 60:75–81 [CrossRef]
    [Google Scholar]
  41. Lambers H, Piessens S, Bloem A, Pronk H, Finkel P. Natural skin surface pH is on average below 5, which is beneficial for its resident flora. Int J Cosmet Sci 2006; 28:359–370 [CrossRef]
    [Google Scholar]
  42. Fischer H, Widdicombe JH. Mechanisms of acid and base secretion by the airway epithelium. J Membrane Biol 2006; 211:139–150 [CrossRef]
    [Google Scholar]
  43. Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A et al. Biology of Zika virus infection in human skin cells. J Virol 2015; 89:8880–8896 [CrossRef]
    [Google Scholar]
  44. Pingen M, Schmid MA, Harris E, McKimmie CS. Mosquito biting modulates skin response to virus infection. Trends Parasitol 2017; 33:645–657 [CrossRef]
    [Google Scholar]
  45. Mühlebach MD, Mateo M, Sinn PL, Prüfer S, Uhlig KM et al. Adherens junction protein Nectin-4 is the epithelial receptor for measles virus. Nature 2011; 480:530–533 [CrossRef]
    [Google Scholar]
  46. Proksch E. pH in nature, humans and skin. J Dermatol 2018; 45:1044–1052 [CrossRef]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001472
Loading
/content/journal/jgv/10.1099/jgv.0.001472
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error