A BACTERIOPHAGE /ˈbækˈtɪər.i.oʊˌfeɪdʒ/ , also known
informally as a PHAGE /ˈfeɪdʒ/ , is a virus that infects and
replicates within a bacterium . The term is derived from "bacteria"
and the Greek : φαγεῖν (phagein), "to devour". Bacteriophages
are composed of proteins that encapsulate a
RNA genome , and
may have relatively simple or elaborate structures. Their genomes may
encode as few as four genes, and as many as hundreds of genes . Phages
replicate within the bacterium following the injection of their genome
into its cytoplasm . Bacteriophages are among the most common and
diverse entities in the biosphere . Bacteriophages are ubiquitous
viruses, found wherever bacteria exist. It’s estimated there are
more than 1031 bacteriophages on the planet, more than every other
organism on Earth, including bacteria, combined.
Phages are widely distributed in locations populated by bacterial
hosts, such as soil or the intestines of animals. One of the densest
natural sources for phages and other viruses is sea water, where up to
9×108 virions per milliliter have been found in microbial mats at the
surface, and up to 70% of marine bacteria may be infected by phages.
They have been used for over 90 years as an alternative to antibiotics
in the former
Soviet Union and Central Europe, as well as in France.
They are seen as a possible therapy against multi-drug-resistant
strains of many bacteria (see phage therapy ). Nevertheless, phages
Inoviridae have been shown to complicate biofilms involved in
pneumonia and cystic fibrosis, and shelter the bacteria from drugs
meant to eradicate disease and promote persistent infection.
* 1 Classification
* 2 History
* 4 Replication
* 4.1 Attachment and penetration
* 4.2 Synthesis of proteins and nucleic acid
* 4.3 Virion assembly
* 4.4 Release of virions
* 6 Systems biology
* 7 In the environment
* 8 Other areas of use
* 9 Model bacteriophages
* 10 See also
* 11 References
* 12 External links
Bacteriophages occur abundantly in the biosphere, with different
virions, 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
and only five families are enveloped. Of the viral families with DNA
genomes, only two have single-stranded genomes. Eight of the viral
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.
Bacteriophage P22, a member of the
Podoviridae by morphology due to
its short, non-contractile tail.
ICTV CLASSIFICATION OF PROKARYOTIC (BACTERIAL AND ARCHAEAL) VIRUSES
Nonenveloped , contractile tail
T4 phage , Mu , PBSX, P1Puna-like, P2, I3, Bcep 1, Bcep 43, Bcep 78
Nonenveloped, noncontractile tail (long)
λ phage , T5 phage , phi, C2, L5,
HK97 , N15
Nonenveloped, noncontractile tail (short)
T7 phage ,
T3 phage , Φ29 , P22, P37
Acidianus filamentous virus 1
Sulfolobus islandicus rod-shaped virus 1
MS2 , Qβ
Ernest Hanbury Hankin reported that something in the waters
Yamuna rivers in
India had marked antibacterial
action against cholera and could pass through a very fine porcelain
filter. 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:
* a stage in the life cycle of the bacteria;
* an enzyme produced by the bacteria themselves; or
* a virus that grew on and destroyed the bacteria.
Twort's work was interrupted by the onset of
World War I
World War I and shortage
of funding. Independently,
French-Canadian microbiologist Félix
d\'Hérelle , working at the
Pasteur Institute in
Paris , announced on
3 September 1917, that he had discovered "an invisible, antagonistic
microbe of the dysentery bacillus". For d’Hérelle, there was no
question as to the nature of his discovery: "In a flash I had
understood: what caused my clear spots was in fact an invisible
microbe … a virus parasitic on bacteria." D'Hérelle called the
virus a bacteriophage or bacteria-eater (from the Greek phagein
meaning to eat). He also recorded a dramatic account of a man
suffering from dysentery who was restored to good health by the
bacteriophages. It was D'Herelle who conducted much research into
bacteriophages and introduced the concept of phage therapy .
Max Delbrück ,
Alfred Hershey and
Salvador Luria were
Nobel Prize in Physiology or Medicine for their
discoveries of the replication of viruses and their genetic structure.
Phages were discovered to be antibacterial agents and were used in
Soviet Republic of Georgia (pioneered there by Giorgi
Eliava with help from the co-discoverer of bacteriophages, Felix
d'Herelle) and the
United States 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:
* Medical trials were carried out, but a basic lack of understanding
of phages made these invalid.
* Antibiotics were discovered and marketed widely. They were easier
to make, store and to prescribe.
Soviet research continued, but publications were mainly in
Russian or Georgian languages and were unavailable internationally for
Their use has continued since the end of the Cold War in 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 leg ulcers in human
patients. 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 explain that the
use of certain chemicals that are part of standard wound care (e.g.
lactoferrin or silver) may have interfered with bacteriophage
viability. Another controlled clinical trial in Western Europe
(treatment of ear infections caused by Pseudomonas aeruginosa) was
reported shortly after in the journal Clinical Otolaryngology in
August 2009. 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. Meanwhile, bacteriophage
researchers are developing engineered viruses to overcome antibiotic
resistance, and engineering the phage genes responsible for coding
enzymes which degrade the biofilm matrix, phage structural proteins
and also enzymes responsible for lysis of bacterial cell wall.
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." This includes
rivers traditionally thought to have healing powers, including India's
Diagram of the
DNA injection process
Bacteriophages may have a lytic cycle or a lysogenic cycle , and a
few viruses are capable of carrying out both. With lytic phages such
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 phage going dormant and is usually temporary.
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
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 of the cell’s
offspring. An example of a bacteriophage known to follow the lysogenic
cycle and the lytic cycle is the phage lambda of E. coli.
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, which cause diphtheria or
cholera , respectively. Strategies to combat certain bacterial
infections by targeting these toxin-encoding prophages have been
ATTACHMENT AND PENETRATION
In this electron micrograph of bacteriophages attached to a
bacterial cell, the viruses are the size and shape of coliphage T1.
To enter a host cell, bacteriophages attach to specific receptors on
the surface of bacteria, including lipopolysaccharides , teichoic
acids , proteins , or even flagella . This specificity means a
bacteriophage can infect only certain bacteria bearing receptors to
which they can bind, which in turn determines the phage's host range.
Host growth conditions also influence the ability of the phage to
attach and invade them. As phage virions do not move independently,
they must rely on random encounters with the right receptors when in
solution (blood, lymphatic circulation, irrigation, soil water, etc.).
Myovirus bacteriophages use a hypodermic syringe -like motion to
inject their genetic material into the cell. After making contact with
the appropriate receptor, the tail fibers flex to bring the base plate
closer to the surface of the cell; this is known as reversible
binding. Once attached completely, irreversible binding is initiated
and the tail contracts, possibly with the help of ATP present in the
tail, injecting genetic material through the bacterial membrane.
Podoviruses lack an elongated tail sheath similar to that of a
myovirus, so they instead use their small, tooth-like tail fibers
enzymatically to degrade a portion of the cell membrane before
inserting their genetic material.
SYNTHESIS OF PROTEINS AND NUCLEIC ACID
Within minutes, bacterial ribosomes start translating viral m
protein. For RNA-based phages,
RNA replicase is synthesized early in
the process. Proteins modify the bacterial
RNA polymerase so it
preferentially transcribes viral mRNA. The host’s normal synthesis
of proteins and nucleic acids is disrupted, and it is forced to
manufacture viral products instead. These products go on to become
part of new virions within the cell, helper proteins that help
assemble the new virions, or proteins involved in cell lysis . Walter
University of Ghent ,
Belgium ) was the first to establish the
complete nucleotide sequence of a gene (1972) and of the viral genome
of bacteriophage MS2 (1976).
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. Diagram of a typical tailed
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
phages , 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
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 .
Given the millions of different phages in the environment, phages'
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
phages 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.
Bacteriophage genomes can be highly mosaic , i.e. the genome of many
phage species appear to be composed of numerous individual modules.
These modules may be found in other phage species in different
arrangements. Mycobacteriophages – bacteriophages with mycobacterial
hosts – have provided excellent examples of this mosaicism. In these
mycobacteriophages, genetic assortment may be the result of repeated
instances of site-specific recombination and illegitimate
recombination (the result of phage genome acquisition of bacterial
host genetic sequences). It should be noted, however, that
evolutionary mechanisms shaping the genomes of bacterial viruses vary
between different families and depend on the type of the nucleic acid,
characteristics of the virion structure, as well as the mode of the
viral life cycle.
Phages 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
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 are most likely several key
interactions and many indirect interactions whose role remains
IN THE ENVIRONMENT
Metagenomics has allowed the in-water detection of bacteriophages
that was not possible previously.
Bacteriophages have also 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. Non-polluted water may contain
ca. 2×108 bacteriophages per mL.
Bacteriophages are thought to extensively contribute to horizontal
gene transfer in natural environments, principally via transduction
but also via transformation .
Metagenomics -based studies have also
revealed that viromes from a variety of environments harbor antibiotic
resistance genes, including those that could confer multidrug
OTHER AREAS OF USE
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,
giving them generally recognized as safe (GRAS) status. In July 2007,
the same bacteriophage were approved for use on all food products. In
2011 USDA confirmed that LISTEX is a clean label processing aid and is
included in USDA. 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.
In 2011 the FDA cleared the first bacteriophage-based product for in
vitro diagnostic use. 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 5 hours, compared to 2–3 days for
standard microbial identification and susceptibility test methods. It
was the first accelerated antibiotic susceptibility test approved by
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
. Developments are continuing among research groups in the US. 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 show success in
veterinary treatment of pet dogs with otitis .
Phage display is a different use of phages involving a library of
phages with a variable peptide linked to a surface protein. Each
phage's 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 can 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
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.
Phage-ligand technology makes use of proteins, which are identified
from bacteriophages, characterized and recombinantly expressed for
various applications such as binding of bacteria and bacterial
components (e.g. endotoxin ) and lysis of bacteria.
Bacteriophages are also important model organisms for studying
principles of evolution and ecology .
The following bacteriophages are extensively studied:
* λ phage
T4 phage (169 kbp genome, 200 nm long )
* R17 phage
MS2 phage (23–28 nm in size )
Enterobacteria phage P2
Phi X 174 phage
* N4 phage
Pseudomonas phage Φ6
* 186 phage
* Viruses portal
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