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Bacteriophages are among the most common and diverse entities in the
biosphere.[1] Bacteriophages are ubiquitous viruses, found wherever bacteria
exist. It is estimated there are more than 1031 bacteriophages on the planet, more
than every other organism on Earth, including bacteria, combined.[2] One of the
densest natural sources for phages and other viruses is seawater, where up to
9x108 virions per millilitre have been found in microbial mats at the surface,[3] The structure of a typical myovirus
bacteriophage
and up to 70% of marine bacteria may be infected by phages.[4]
Phages have been used since the late 19th century as an alternative to antibiotics
in the former Soviet Union and Central Europe, as well as in France.[5][6] They
are seen as a possible therapy against multi-drug-resistant strains of many
bacteria (see phage therapy).[7] Phages of Inoviridae have been shown to
complicate biofilms involved in pneumonia and cystic fibrosis and to shelter the
bacteria from drugs meant to eradicate disease, thus promoting persistent
infection.[8]
Classification
History
Uses
Phage therapy
Other
Replication
Attachment and penetration
Synthesis of proteins and nucleic acid
Virion assembly
Release of virions
Communication
Genome structure
Systems biology
In the environment
Model bacteriophages
See also
References
External links
Classification
Bacteriophages occur abundantly in the biosphere, with different genomes, and lifestyles. Phages are classified by the
International Committee on Taxonomy of Viruses (ICTV) according to morphology and nucleic acid.
Nineteen families are currently recognized by the ICTV that infect bacteria and archaea. Of these, only two families have RNA
genomes, and only five families are surrounded by an envelope. Of the viral families with DNA genomes, only two have single-
stranded genomes. Eight of the viral families with DNA genomes have circular genomes, while nine have linear genomes. Nine
families infect bacteria only, nine infect archaea only, and one (Tectiviridae) infects both bacteria and archaea.
Caudovirales Nonenveloped,
Siphoviridae noncontractile tail Linear dsDNA λ, T5, HK97, N15
(long)
Nonenveloped,
Podoviridae noncontractile tail Linear dsDNA T7, T3, Φ29, P22
(short)
Enveloped, rod- Acidianus
Lipothrixviridae Linear dsDNA
shaped filamentous virus 1
Ligamenvirales
Nonenveloped, rod- Sulfolobus islandicus
Rudiviridae Linear dsDNA
shaped rod-shaped virus 1
Unassigned Enveloped, bottle-
Ampullaviridae Linear dsDNA
shaped
Nonenveloped,
Bicaudaviridae Circular dsDNA
lemon-shaped
Nonenveloped, rod-
Clavaviridae Circular dsDNA
shaped
Nonenveloped,
Corticoviridae Circular dsDNA PM2
isometric
Cystoviridae Enveloped, spherical Segmented dsRNA
Nonenveloped,
Fuselloviridae Circular dsDNA
lemon-shaped
Globuloviridae Enveloped, isometric Linear dsDNA
Nonenveloped,
Guttaviridae Circular dsDNA
ovoid
Nonenveloped,
Inoviridae Circular ssDNA M13
filamentous
Nonenveloped,
Leviviridae Linear ssRNA MS2, Qβ
isometric
Nonenveloped,
Microviridae Circular ssDNA ΦX174
isometric
Enveloped,
Plasmaviridae Circular dsDNA
pleomorphic
Enveloped, Circular ssDNA, circular
Pleolipoviridae
pleomorphic dsDNA, or linear dsDNA
Portogloboviridae Enveloped, isometric Circular dsDNA
Sphaerolipoviridae Enveloped, isometric Linear dsDNA
Nonnveloped, rod-
Spiraviridae Circular ssDNA
shaped
Nonenveloped,
Tectiviridae Linear dsDNA
isometric
Tristromaviridae Enveloped, rod- Linear dsDNA
shaped
Turriviridae Enveloped, isometric Linear dsDNA
It has been suggested that members of Picobirnaviridae infect bacteria, but not mammals.[9]
History
In 1896, Ernest Hanbury Hankin reported that something in the waters of the Ganges and Yamuna rivers in India had a marked
antibacterial action against cholera and it could pass through a very fine porcelain filter.[10] In 1915, British bacteriologist
Frederick Twort, superintendent of the Brown Institution of London, discovered a small agent that infected and killed bacteria. He
believed the agent must be one of the following:
More than a half a century later, in 1969, Max Delbrück, Alfred Hershey, and
Salvador Luria were awarded the Nobel Prize in Physiology or Medicine for
their discoveries of the replication of viruses and their genetic structure.[15]
Phage therapy
Phages were discovered to be antibacterial agents and were used in the former Soviet Republic of Georgia (pioneered there by
Giorgi Eliava with help from the co-discoverer of bacteriophages, Félix d'Herelle) during the 1920s and 1930s for treating
bacterial infections. They had widespread use, including treatment of soldiers in the Red Army. However, they were abandoned
for general use in the West for several reasons:
Antibiotics were discovered and marketed widely. They were easier to make, store, and to prescribe.
Medical trials of phages were carried out, but a basic lack of understanding raised questions about the validity of
these trials.[16]
Publication of research in the Soviet Union was mainly in the Russian or Georgian languages and for many
years, was not followed internationally.
The use of phages has continued since the end of the Cold War in Russia[17], Georgia and elsewhere in Central and Eastern
Europe. The first regulated, randomized, double-blind clinical trial was reported in the Journal of Wound Care in June 2009,
which evaluated the safety and efficacy of a bacteriophage cocktail to treat infected venous ulcers of the leg in human
patients.[18] The FDA approved the study as a Phase I clinical trial. The study's results demonstrated the safety of therapeutic
application of bacteriophages, but did not show efficacy. The authors explained that the use of certain chemicals that are part of
standard wound care (e.g. lactoferrin or silver) may have interfered with bacteriophage viability.[18] Shortly after that, another
controlled clinical trial in Western Europe (treatment of ear infections caused by Pseudomonas aeruginosa) was reported in the
journal, Clinical Otolaryngology in August 2009.[19] The study concludes that bacteriophage preparations were safe and effective
for treatment of chronic ear infections in humans. Additionally, there have been numerous animal and other experimental clinical
trials evaluating the efficacy of bacteriophages for various diseases, such as infected burns and wounds, and cystic fibrosis
associated lung infections, among others.[19]
Meanwhile, bacteriophage researchers have been developing engineered viruses to overcome antibiotic resistance, and
engineering the phage genes responsible for coding enzymes that degrade the biofilm matrix, phage structural proteins, and the
enzymes responsible for lysis of the bacterial cell wall.[3][4][5] There have been results showing that T4 phages that are small in
size and short-tailed, can be helpful in detecting E.coli in the human body.[20]
Therapeutic efficacy of a phage cocktail was evaluated in a mice model with nasal infection of multidrug-resistant (MDR) A.
baumannii. Mice treated with the phage cocktail showed a 2.3-fold higher survival rate than those untreated in seven days post
infection.[21] In 2017 a patient with a pancreas compromised by MDR A. baumannii was put on several antibiotics, despite this
the patient’s health continued to deteriorate during a four-month period. Without effective antibiotics the patient was subjected to
phage therapy using a phage cocktail containing nine different phages that had been demonstrated to be effective against MDR A.
baumannii. Once on this therapy the patient’s downward clinical trajectory reversed, and returned to health.[22]
D'Herelle "quickly learned that bacteriophages are found wherever bacteria thrive: in sewers, in rivers that catch waste runoff
from pipes, and in the stools of convalescent patients."[23] This includes rivers traditionally thought to have healing powers,
including India's Ganges River.[24]
Other
Food industry - Since 2006, the United States Food and Drug Administration (FDA) and United States Department of
Agriculture (USDA) have approved several bacteriophage products. LMP-102 (Intralytix) was approved for treating ready-to-eat
(RTE) poultry and meat products. In that same year, the FDA approved LISTEX (developed and produced by Micreos) using
bacteriophages on cheese to kill Listeria monocytogenes bacteria, in order to give them generally recognized as safe (GRAS)
status.[25] In July 2007, the same bacteriophage were approved for use on all food products.[26] In 2011 USDA confirmed that
LISTEX is a clean label processing aid and is included in USDA.[27] Research in the field of food safety is continuing to see if
lytic phages are a viable option to control other food-borne pathogens in various food products.
Dairy industry - Bacteriophages present in the environment can cause fermentation failures of cheese starter cultures. In order to
avoid this, mixed-strain starter cultures and culture rotation regimes can be used.[28]
Diagnostics - In 2011, the FDA cleared the first bacteriophage-based product for in vitro diagnostic use.[29] The KeyPath
MRSA/MSSA Blood Culture Test uses a cocktail of bacteriophage to detect Staphylococcus aureus in positive blood cultures and
determine methicillin resistance or susceptibility. The test returns results in about five hours, compared to two to three days for
standard microbial identification and susceptibility test methods. It was the first accelerated antibiotic-susceptibility test approved
by the FDA.[30]
Counteracting bioweapons and toxins - Government agencies in the West have for several years been looking to Georgia and
the former Soviet Union for help with exploiting phages for counteracting bioweapons and toxins, such as anthrax and
botulism.[31] Developments are continuing among research groups in the U.S. Other uses include spray application in horticulture
for protecting plants and vegetable produce from decay and the spread of bacterial disease. Other applications for bacteriophages
are as biocides for environmental surfaces, e.g., in hospitals, and as preventative treatments for catheters and medical devices
before use in clinical settings. The technology for phages to be applied to dry surfaces, e.g., uniforms, curtains, or even sutures
for surgery now exists. Clinical trials reported in Clinical Otolaryngology[19] show success in veterinary treatment of pet dogs
with otitis.
The SEPTIC bacterium sensing and identification method uses the ion emission and its dynamics during phage infection and
offers high specificity and speed for detection.[32]
Phage display is a different use of phages involving a library of phages with a variable peptide linked to a surface protein. Each
phage genome encodes the variant of the protein displayed on its surface (hence the name), providing a link between the peptide
variant and its encoding gene. Variant phages from the library may be selected through their binding affinity to an immobilized
molecule (e.g., botulism toxin) to neutralize it. The bound, selected phages can be multiplied by reinfecting a susceptible bacterial
strain, thus allowing them to retrieve the peptides encoded in them for further study.[33]
Antimicrobial drug discovery - Phage proteins often have antimicrobial activity and may serve as leads for peptidomimetics,
i.e. drugs that mimic peptides.[34] Phage-ligand technology makes use of phage proteins for various applications, such as binding
of bacteria and bacterial components (e.g. endotoxin) and lysis of bacteria.[35]
Basic research - Bacteriophages are important model organisms for studying principles of evolution and ecology.[36]
Replication
Bacteriophages may have a lytic cycle or a lysogenic cycle, and a few viruses
are capable of carrying out both. With lytic phages such as the T4 phage,
bacterial cells are broken open (lysed) and destroyed after immediate replication
of the virion. As soon as the cell is destroyed, the phage progeny can find new
hosts to infect. Lytic phages are more suitable for phage therapy. Some lytic
phages undergo a phenomenon known as lysis inhibition, where completed
phage progeny will not immediately lyse out of the cell if extracellular phage
concentrations are high. This mechanism is not identical to that of temperate
Diagram of the DNA injection
phage going dormant and usually, is temporary. process
In contrast, the lysogenic cycle does not result in immediate lysing of the host
cell. Those phages able to undergo lysogeny are known as temperate phages. Their viral genome will integrate with host DNA
and replicate along with it, relatively harmlessly, or may even become established as a plasmid. The virus remains dormant until
host conditions deteriorate, perhaps due to depletion of nutrients, then, the endogenous phages (known as prophages) become
active. At this point they initiate the reproductive cycle, resulting in lysis of the host cell. As the lysogenic cycle allows the host
cell to continue to survive and reproduce, the virus is replicated in all offspring of the cell. An example of a bacteriophage known
to follow the lysogenic cycle and the lytic cycle is the phage lambda of E. coli.[37]
Sometimes prophages may provide benefits to the host bacterium while they are dormant by adding new functions to the bacterial
genome, in a phenomenon called lysogenic conversion. Examples are the conversion of harmless strains of Corynebacterium
diphtheriae or Vibrio cholerae by bacteriophages, to highly virulent ones that cause diphtheria or cholera, respectively.[38][39]
Strategies to combat certain bacterial infections by targeting these toxin-encoding prophages have been proposed.[40]
Virion assembly
In the case of the T4 phage, the construction of new virus particles involves the assistance of helper proteins. The base plates are
assembled first, with the tails being built upon them afterward. The head capsids, constructed separately, will spontaneously
assemble with the tails. The DNA is packed efficiently within the heads. The whole process takes about 15 minutes.
Release of virions
Phages may be released via cell lysis, by extrusion, or, in a few cases, by budding. Lysis, by tailed phages, is achieved by an
enzyme called endolysin, which attacks and breaks down the cell wall peptidoglycan. An altogether different phage type, the
filamentous phage, make the host cell continually secrete new virus particles. Released virions are described as free, and, unless
defective, are capable of infecting a new bacterium. Budding is associated with certain Mycoplasma phages. In contrast to virion
release, phages displaying a lysogenic cycle do not kill the host but, rather, become long-term residents as prophage.
Communication
Research in 2019 revealed that the bacteriophage Φ3T makes a short viral protein that signals other bacteriophages to lie dormant
instead of killing the host bacterium. Arbitrium is the name given to this protein by the researchers who discovered it.[45][46]
Genome structure
Given the millions of different phages in the environment, phage
genomes come in a variety of forms and sizes. RNA phage such
as MS2 have the smallest genomes, of only a few kilobases.
However, some DNA phage such as T4 may have large genomes
with hundreds of genes; the size and shape of the capsid varies
along with the size of the genome.[47]
Systems biology
Phage often have dramatic effects on their hosts. As a consequence, the transcription pattern of the infected bacterium may
change considerably. For instance, infection of Pseudomonas aeruginosa by the temperate phage PaP3 changed the expression of
38% (2160/5633) of its host's genes. Many of these effects are probably indirect, hence the challenge becomes to identify the
direct interactions among bacteria and phage.[50]
Several attempts have been made to map protein–protein interactions among phage and their host. For instance, bacteriophage
lambda was found to interact with its host, E. coli, by 31 interactions. However, a large-scale study revealed 62 interactions, most
of which were new. Again, the significance of many of these interactions remains unclear, but these studies suggest that there
most likely are several key interactions and many indirect interactions whose role remains uncharacterized.[51]
In the environment
Metagenomics has allowed the in-water detection of bacteriophages that was not possible previously.[52]
Also, bacteriophages have been used in hydrological tracing and modelling in river systems, especially where surface water and
groundwater interactions occur. The use of phages is preferred to the more conventional dye marker because they are significantly
less absorbed when passing through ground waters and they are readily detected at very low concentrations.[53] Non-polluted
water may contain approximately 2×108 bacteriophages per mL.[54]
Bacteriophages are thought to contribute extensively to horizontal gene transfer in natural environments, principally via
transduction, but also via transformation.[55] Metagenomics-based studies also have revealed that viromes from a variety of
environments harbor antibiotic-resistance genes, including those that could confer multidrug resistance.[56]
Model bacteriophages
The following bacteriophages are extensively studied:
186 phage
λ phage
Φ6 phage
Φ29 phage
ΦX174
G4 phage
M13 phage
MS2 phage (23–28 nm in size)[57]
N4 phage
P1 phage
P2 phage
P4 phage
R17 phage
T2 phage
T4 phage (169 kbp genome,[58] 200 nm long[59])
T7 phage
T12 phage
See also
Bacterivore
CrAssphage
DNA viruses
Phage ecology
Phage monographs (a comprehensive listing of phage and phage-associated monographs, 1921 – present)
Polyphage
RNA viruses
Transduction
Viriome
CRISPR
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External links
Häusler, T. (2006) "Viruses vs. Superbugs", Macmillan (http://www.thomashausler.com/viruses-vs-superbugs/)
Animation of bacteriophage targeting E. coli bacteria (https://web.archive.org/web/20160303215841/http://www.e
gilsjolander.com/E_coli.mp4)
Phage.org general information on bacteriophages (https://web.archive.org/web/20130603163753/http://www.pha
ge.org/)
bacteriophages illustrations and genomics (http://bacteriophages.igmors.u-psud.fr/)
Bacteriophages get a foothold on their prey (http://www.ebi.ac.uk/pdbe/widgets/QuipStories/T4tail/T4tail.pdf)
NPR Science Friday podcast, "Using 'Phage' Viruses to Help Fight Infection", April 2008 (https://web.archive.org/
web/20080417232145/http://www.sciencefriday.com/program/archives/200804043)
Animation of a scientifically correct T4 bacteriophage targeting E. coli bacteria (https://www.youtube.com/watch?v
=V73nEGXUeBY)
Animation by Hybrid Animation Medical for a T4 Bacteriophage targeting E. coli bacteria (https://vimeo.com/8313
889)
Bacteriophages: What are they. Presentation by Professor Graham Hatfull, University of Pittsburgh (https://www.y
outube.com/watch?v=3VjE1zddXWk) on YouTube
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