# Berna Hanım ACUN: ***Bacteriophage, Biology,Technology Therapy by David Harper (2018)***

# CONTENTS
:::danger
1.INTRODUCTION
2.Characteristics of bacteriophages
3.Life cycles of bacteriophages
4.Role in laboratory research
5.Phage therapy
5.1History of phage therapy

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Bacteriophage, also called phage or bacterial virus, 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).

Bacteriophages (BPs) are viruses that can infect and kill bacteria without any negative effect on human or animal cells. For this reason, it is supposed that they can be used, alone or in combination with antibiotics, to treat bacterial infections.

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.

# Lytic cycle

In the lytic cycle, a phage acts like a typical virus: it hijacks its host cell and uses the cell's resources to make lots of new phages, causing the cell to lyse (burst) and die in the process.

The stages of the lytic cycle are:
Attachment: Proteins in the "tail" of the phage bind to a specific receptor (in this case, a sugar transporter) on the surface of the bacterial cell.
Entry: The phage injects its double-stranded DNA genome into the cytoplasm of the bacterium.
DNA copying and protein synthesis: Phage DNA is copied, and phage genes are expressed to make proteins, such as capsid proteins.
Assembly of new phage: Capsids assemble from the capsid proteins and are stuffed with DNA to make lots of new phage particles.
Lysis: Late in the lytic cycle, the phage expresses genes for proteins that poke holes in the plasma membrane and cell wall. The holes let water flow in, making the cell expand and burst like an overfilled water balloon.
Cell bursting, or lysis, releases hundreds of new phages, which can find and infect other host cells nearby. In this way, a few cycles of lytic infection can let the phage spread like wildfire through a bacterial population.

# Lysogenic cycle

The lysogenic cycle allows a phage to reproduce without killing its host. Some phages can only use the lytic cycle, but the phage we are following, lambda (
λ
λlambda), can switch between the two cycles.
In the lysogenic cycle, the first two steps (attachment and DNA injection) occur just as they do for the lytic cycle. However, once the phage DNA is inside the cell, it is not immediately copied or expressed to make proteins. Instead, it recombines with a particular region of the bacterial chromosome. This causes the phage DNA to be integrated into the chromosome.

The integrated phage DNA, called a prophage, is not active: its genes aren't expressed, and it doesn't drive production of new phages. However, each time a host cell divides, the prophage is copied along with the host DNA, getting a free ride. The lysogenic cycle is less flashy (and less gory) than the lytic cycle, but at the end of the day, it's just another way for the phage to reproduce.
Under the right conditions, the prophage can become active and come back out of the bacterial chromosome, triggering the remaining steps of the lytic cycle (DNA copying and protein synthesis, phage assembly, and lysis).

# 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.

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