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Antiviral Drug Triggers Cell to Eat Itself

A chief weapon cells possess against infection is the ability to commit suicide. Obviously, suicide kills the cell, but it usually kills the invading microbe, as well. Thus, in multicellular organisms, individual cells "take one for the team" -- ending their own lives for the benefit of the organism as a whole, and the cell has multiple suicide options at its disposal.

Apoptosis is the best-known mechanism of cellular suicide. (Note: The second "p" is silent.) While apoptosis is often associated with developmental purposes (e.g., a tadpole losing its tail as it becomes an adult frog), this mechanism also serves an important immune function: Cytotoxic T-cells can trigger apoptosis in body cells which have become infected. For the most part, the death is quick and silent: the DNA is chopped up, and the cell shrivels and fragments into many pieces which are gobbled up by phagocytes.

Pyroptosis is a bit different. (Yes, the second "p" is silent here, too.) Think of "pyromaniacs" -- the people who set fires on purpose. Death by pyroptosis is sort of like that. An infected cell goes out with a bang, triggering inflammation and letting the immune system know that something horrible just happened. It serves as something of a wake-up call, moving the immune system to action.

Or... a cell could eat itself. This option is called autophagy, and like apoptosis, it is often associated with normal developmental processes and fighting infections. The cell fragments into small pieces internally and digests itself from within. Whatever is left over is cleaned up by phagocytes.

Now, researchers report in Nature the discovery of a potential therapeutic agent that triggers autophagy in virus-infected cells.

Aedes_aegypti_biting_human.jpgThe authors found that a peptide (short protein) called Tat-Beclin 1 was a strong inducer of autophagy. If applied to HeLa cells infected with three different viruses (Sindbis, Chikungunya, or West Nile -- all of which are transmitted by mosquitoes), the peptide greatly reduced the ability of the viruses to reproduce. The peptide also greatly reduced the ability of HIV to replicate in human macrophage cells. 

Encouraged by these results, the authors moved into a live mouse model, using the Chikungunya and West Nile viruses. The authors wanted to determine if triggering autophagy with Tat-Beclin 1 would rescue mice given a lethal dose of virus. Indeed, it worked, albeit modestly. Both viruses killed 100% of untreated mice. However, 37.5% of Chikungunya-infected and roughly 20% of West Nile-infected mice survived if treated with the therapeutic peptide.

These results clearly imply that autophagy inducing agents can be used as antivirals. Additionally, since autophagy also plays a role in normal developmental processes, the authors hope that autophagy inducing agents could be used to treat a wide variety of medical problems.

Source: Sanae Shoji-Kawata, et al. "Identification of a candidate therapeutic autophagy-inducing peptide." Nature 2013. Published online 30 Jan 2013. doi: 10.1038/nature11866

Background: Susan L. Fink and Brad T. Cookson. "Apoptosis, Pyroptosis, and Necrosis: Mechanistic Description of Dead and Dying Eukaryotic Cells." Infect Immun 2005. April; 73(4): 1907-1916. doi: 10.1128/IAI.73.4.1907-1916.2005

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