Bacterial viruses -- bacteriophages, also called “phages” -- are a group of viruses that infect and kill only bacteria. They are distinct from viruses that infect animals or plants.

Phages can have either a lytic lifestyle or a lysogenic one. Those with a lytic lifestyle infect a host cell, kill it, and then begin replicating to the point that the cell ruptures, or lyses. Those phages with a lysogenic lifestyle infect a host cell with DNA and can then lie dormant, choosing when to reactivate and destroy the cell. Our main interest in this article is the lytic viruses -- the efficient bacterial killers!

The life cycle of a lytic phage is diagrammed above, in Figure 1. First, the lytic phage must identify its specific host. This process can take a bit of trial and error. The way the virus finds its host is through protein fibers at the end of its tail. Essentially the tail fibers "feel" their way across the outside surface of the cell wall looking for a specific protein or other compound that specifically matches the proteins at the end of the tail fiber. A good analogy is a “lock and key.” The “key” is the end of the tail fiber, and the “lock” is the specific cell wall compound. When the key finds its lock, the virus permanently attaches to the cell wall using all of its tail fibers.

The phage then contracts the outside of its tail, which pushes a stiff tube located inside through the cell wall and inner membrane of the bacterial cell. In effect, the tail injects a needle into the cell. Once the needle has pierced the cell wall, the virus pushes its genetic material (DNA or RNA) through the needle and into the cell (see Fig. 2 and a Quicktime movie). The viral genes quickly take over the cell’s machinery to make more copies of itself. Once the bacterial cell is stuffed full of viruses, the cell ruptures, or lyses, and releases hundreds of virus particles, which are capable of infecting hundreds of new host cells. For some phages, this process happens in the span of 30 minutes!

Two aspects of lytic phages make them attractive as "drugs" to fight bacterial infections. First, their "lock and key" nature means that a lytic virus can only infect a specific bacterial species. It also means that phage do not attack and infect any other cell types, including human ones. Because phage are very specific in to the types of bacteria they infect, it is possible to find a group of different phages that are capable of attacking and killing only a single bacterial species or strain and not all bacteria. In contrast, chemical antibiotics kill all bacteria, including the good ones!

Second, because phages can grow so fast, this bacteria-killing drug actually makes more of itself at the site of infection! This means that maybe only one dose of the drug would be necessary instead of taking pills every day for a week or more.

Before the discovery of modern chemical antibiotics, phages were used to cure bacterial infections. Sometimes phages worked well, and other times they failed. We now know that bacteria can become resistant to their phages by changing the "locks" on the outside of their cell wall. After many decades of using chemical antibiotics, we are now finding bacteria that are resistant to these wonder drugs. Because there are more and more bacteria that are resistant to even our best chemical antibiotics, scientists are once again looking to phages as a way to fight the bacteria that cause infections.

The idea to use phages as drugs against bacteria is nearly 100 years old. Two scientists -- Edward Twort (1915), a British bacteriologist, and Felix d'Herelle (1917), a self-taught biologist working at the Pasteur Institute in Paris -- discovered a mysterious entity smaller than a bacterium that was able to destroy bacterial cells. Felix d’ Herelle carefully studied these tiny agents, which he called "bacteriophages" and found that they could selectively kill bacteria which caused a deadly form of diarrhea called dysentery. In his time, bacterial dysentery killed thousands of people each year, especially soldiers on the battlefield. His early experiments were the beginning of the phage therapy.

In the next decades, phage therapy was used in many countries to treat millions of patients against infectious diseases like cholera, and dysentery, particularly during World War II. With the discovery of "penicillin" by Alexander Fleming in 1928 and its later development as a drug to treat bacterial infections in the 1940s, pharmaceutical companies abandoned phage therapy in favor of chemical antibiotics. However, phage therapy continued in Russia and surrounding countries.

We owe a lot to chemical antibiotics. These wonder drugs have saved millions of lives; however, because bacteria are now showing resistance to chemical antibiotics, scientists are again looking to lytic phage as an alternative way of curing bacterial infection.

More comprehensive information on phage therapy can be found on this Evergreen State College Web site.

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References:
1. Carlton, R. M. 1999. Phage therapy: past history and future prospects. Arch Immunol Ther Exp (Warsz) 47:267-74.
2. Projan, S. 2004. Phage-inspired antibiotics? Nat. Biotechnol. 22:167-168.
3. Sulakvelidze, and. Kutter, E. 2004. Bacteriophage therapy in humans. In Bacteriophages: Biology and Application (E. Kutter and A. Sulakvelidze, eds), 381–436.
4. Summers, W. C. 2001. Bacteriophage therapy. Annu. Rev. Microbiol. 55:437-451.