Thursday, December 1, 2016

Could an antiviral from “the good old days” hold the secret to curing the common cold?

Penicillins were first discovered in the mid-1940s, and they revolutionized medicine. Formerly fatal antibiotic infections became curable. After the discovery of penicillin, however, much of the research on other antibiotic treatments stopped. Since bacterial infections were now curable, why would we need another option? Prior to the advent of penicillins, however, certain chemical dyes were used as antiseptics. In a groundbreaking study published in September of this year, Pépin et al. (2016) observed that acriflavine and proflavine, two of these dyes, could significantly reduce rhinovirus infection in human bronchial cells. In other words, these Prohibition-era antiseptics may work as modern antivirals.

The researchers started their work in mouse cells. They treated the cells with a mixture of acriflavine and proflavine, which they referred to simply as “flavine,” and then infected the cells with Semlikiforest virus (SFV), an African virus transmitted by mosquito bites. Surprisingly, the flavine treatment activated a type-I interferon (IFN) antiviral response, meaning that it encouraged the mouse’s own immune system to fight the virus.

After the encouraging results observed in mouse cells, the researchers moved on to working with human cells. They tested several types of cells including fibroblasts (cells that synthesize collagen, an important protein for tendons, ligaments, skin, and many other organs) and bronchial cells (cells from the bronchus, which carries air into the lungs). The results continued to look promising, as all of the different types of human cells showed evidence of a type-I IFN response.

Unfortunately, not all results were so fortunate. From prior research, the researchers knew that flavine inserts itself into DNA (Hassan et al., 2011). When they observed the mouse fibroblasts treated with flavine, they saw similar evidence of DNA damage. In addition, they noticed that DNA was leaking from the nucleus, the “brain” of the cell where DNA is usually located, into the cytoplasm, the “body” of the cell. Below, I have included a picture of the DNA leakage. The white arrows indicate cytoplasmic DNA.
After treatment with flavine, researchers observed leakage of the DNA (green) from the nuclei (circles) of these mouse fibroblast cells.

Finally, to determine the mechanism behind flavine’s antiviral properties, the researchers first tested knocking out certain cellular signals and testing whether flavine could still work. They also observed flavine’s effects on the levels of various cellular proteins. They discovered that flavine causes a cellular signaling cascade to occur, activating one signal, which activates another, and so on until an antiviral IFN response occurs. However, too much flavine is simply toxic to cells. An image of this pathway is below. Flavine works by activating cGAS, which in turn activates TBK1, which activates IRF3, which finally leads to the activation of IFN and an antiviral response.
The signal cascade that leads to the production of interferon (IFN) to fight virus infection.

So how useful is flavine as a potential therapeutic? Despite flavine’s DNA-damaging effects on cells, acriflavine and proflavine were both used for over 50 years with no evidence of carcinogenic effects, suggesting that flavine might still be safe for clinical use. Since this dye has been found to be effective against the rhinovirus, we just might be looking at a potential cure for the common cold.

(Note: All sources are also linked in text.)
  • Browning, C. H. "Proflavine and Acriflavine." Bmj 2.5544 (1967): 111. Web.
  • Hassan, Saadia, Daniel Laryea, Haile Mahteme, Jenny Felth, Marten Fryknas, Walid Fayad, Stig Linder, Linda Rickardson, Joachim Gullbo, Wilhelm Graf, Lars Pahlman, Bengt Glimelius, Rolf Larsson, and Peter Nygren. "Novel Activity of Acriflavine against Colorectal Cancer Tumor Cells." Cancer Science 102.12 (2011): 2206-213. Web.
  • "Institutional Links." Semliki Forest Virus - Pathogen Safety Data Sheets. N.p., n.d. Web. 01 Dec. 2016.
  • Miller, Elissa Lane. "The penicillins: a review and update." Journal of Midwifery & Women’s Health 47.6 (2002): 426-434.
  • Pepin, Genevieve, Charlotte Nejad, Belinda J. Thomas, Jonathan Ferrand, Kate Mcarthur, Philip G. Bardin, Bryan R.g. Williams, and Michael P. Gantier. "Activation of CGAS-dependent Antiviral Responses by DNA Intercalating Agents." Nucleic Acids Research (2016): n. pag. Web.
  • Image source: http://www.nature.com/nrmicro/journal/v11/n8/images/nrmicro3069-f5.jpg 

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