bacteriophage

bacteriophage, any of a group of viruses that infect bacteria. Bacteriophages were discovered independently by Frederick W. Twort in Great Britain (1915) and Félix d’Hérelle in France (1917). D’Hérelle coined the term bacteriophage, meaning “bacteria eater,” to describe the agent’s bacteriocidal ability. Bacteriophages also infect the single-celled prokaryotic organisms known as archaea.

Characteristics of bacteriophages

Thousands of varieties of phages exist, each of which may infect only one type or a few types of bacteria or archaea. Phages are classified in a number of virus families; some examples include Inoviridae, Microviridae, Rudiviridae, and Tectiviridae. Like all viruses, phages are simple organisms that consist of a core of genetic material (nucleic acid) surrounded by a protein capsid. The nucleic acid may be either DNA or RNA and may be double-stranded or single-stranded. There are three basic structural forms of phage: an icosahedral (20-sided) head with a tail, an icosahedral head without a tail, and a filamentous form.

Life cycles of bacteriophages

During infection a phage attaches to a bacterium and inserts its genetic material into the cell. After that a phage usually follows one of two life cycles, lytic (virulent) or lysogenic (temperate). Lytic phages take over the machinery of the cell to make phage components. They then destroy, or lyse, the cell, releasing new phage particles. Lysogenic phages incorporate their nucleic acid into the chromosome of the host cell and replicate with it as a unit without destroying the cell. Under certain conditions lysogenic phages can be induced to follow a lytic cycle.

Other life cycles, including pseudolysogeny and chronic infection, also exist. In pseudolysogeny a bacteriophage enters a cell but neither co-opts cell-replication machinery nor integrates stably into the host genome. Pseudolysogeny occurs when a host cell encounters unfavourable growth conditions and appears to play an important role in phage survival by enabling the preservation of the phage genome until host growth conditions have become advantageous again. In chronic infection new phage particles are produced continuously over long periods of time but without apparent cell killing.

Role in laboratory research

Phages have played an important role in laboratory research. The first phages studied were those designated type 1 (T1) to type 7 (T7). The T-even phages, T2, T4, and T6, were used as model systems for the study of virus multiplication. In 1952 Alfred Day Hershey and Martha Chase used the T2 bacteriophage in a famous experiment in which they demonstrated that only the nucleic acids of phage molecules were required for their replication within bacteria. The results of the experiment supported the theory that DNA is the genetic material. For his work with bacteriophages, Hershey was awarded the Nobel Prize for Physiology or Medicine in 1969. He shared the award with biologists Salvador Luria and Max Delbrück, whose experiments with the T1 phage in 1943 (the fluctuation test) showed that phage resistance in bacteria was the product of spontaneous mutation and not a direct response to environmental factors. Certain phages, such as lambda, Mu, and M13, are used in recombinant DNA technology. The phage ϕX174 was the first organism to have its entire nucleotide sequence determined, a feat that was accomplished by Frederick Sanger and colleagues in 1977.

In the 1980s American biochemist George P. Smith developed a technology known as phage display, which allowed for the generation of engineered proteins. Such proteins were produced by fusing foreign or engineered DNA fragments into phage gene III. Gene III encodes a protein expressed on the phage virion surface. Thus, gene III fusion proteins taken up by phages were displayed on the surfaces of virion particles. Researchers could then use antibodies developed to recognize the foreign protein fragment to purify fusion phage cultures, thereby effectively amplifying the foreign gene sequence for further study. British biochemist Gregory P. Winter subsequently refined phage display technology for the development of human antibody proteins. Such proteins could be used to treat diseases in humans with less risk of inducing potentially dangerous immune reactions compared with previous therapeutic antibodies derived from animals. Adalimumab (Humira), used for the treatment of rheumatoid arthritis, was the first fully human antibody made via phage display to be approved by the U.S. Food and Drug Administration (approved in 2002). For their discoveries relating to phage display, Smith and Winter were awarded a share of the 2018 Nobel Prize in Chemistry.

Phage therapy

Soon after making their discovery, Twort and d’Hérelle began to use phages in treating human bacterial diseases such as bubonic plague and cholera. Phage therapy was not successful, and after the discovery of antibiotics in the 1940s, it was virtually abandoned. With the rise of antibiotic-resistant bacteria, however, the therapeutic potential of phages has received renewed attention.