This article is about a biological infectious particle; for other uses, see phage (disambiguation).

A bacteriophage (from 'bacteria' and Greek phagein, 'to eat') is any one of a number of viruses that infect bacteria. The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have Greek (el ελληνική γλώσσα or simply el ελληνικά — "Hellenic" is an Indo-European language, spoken today by 15-22 million people mainly A virus (from the Latin virus meaning Toxin or Poison) is a sub-microscopic infectious agent that is unable An infection is the detrimental Colonization of a host Organism by a foreign Species. The term is commonly used in its shortened form, phage.

Typically, bacteriophages consist of an outer protein hull enclosing genetic material. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Genetic material is used to store the genetic information of an organic life form The genetic material can be ssRNA (single stranded RNA), dsRNA, ssDNA, or dsDNA between 5 and 500 kilo base pairs long with either circular or linear arrangement. Ribonucleic acid ( RNA) is a Nucleic acid that consists of a long chain of Nucleotide units Ribonucleic acid ( RNA) is a Nucleic acid that consists of a long chain of Nucleotide units Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known In Molecular biology, two Nucleotides on opposite complementary DNA or RNA strands that are connected via Hydrogen bonds are called Bacteriophages are much smaller than the bacteria they destroy - usually between 20 and 200 nm in size. A nanometre ( American spelling: nanometer, symbol nm) ( Greek: νάνος nanos dwarf; μετρώ metrό count) is a

Phages are estimated to be the most widely distributed and diverse entities in the biosphere. The biosphere is the broadest level of ecological study the global sum of all Ecosystems. ^[1] Phages are ubiquitous and can be found in all reservoirs populated by bacterial hosts, such as soil or the intestines of animals. The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have 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^[2], and up to 70% of marine bacteria may be infected by phages. A virus (from the Latin virus meaning Toxin or Poison) is a sub-microscopic infectious agent that is unable ^[3]

They have been used for over 60 years as an alternative to antibiotics in the former Soviet Union and Eastern Europe. The Union of Soviet Socialist Republics (USSR was a constitutionally Socialist state that existed in Eurasia from 1922 to 1991 ^[4] They are seen as a possible therapy against multi drug resistant strains of many bacteria.

Classification of phages

The dsDNA tailed phages, or Caudovirales, account for 95% of all the phages reported in the scientific literature, and possibly make up the majority of phages on the planet. ^[1] However, there are other phages that occur abundantly in the biosphere, phages with different virions, genomes and lifestyles. Phages are classified by the International Committee on Taxonomy of Viruses (ICTV) according to morphology and nucleic acid. The International Committee on Taxonomy of Viruses ( ICTV) is a committee which authorizes and organizes the taxonomic classification of Viruses They have

History

Since ancient times, there have been documented reports of river water having the ability to cure infectious diseases, such as leprosy. The Caudovirales are an order of Viruses better known as the tailed Bacteriophages. The Myoviridae are a family of Bacteriophages including the following genera Genus T4-like viruses; type species Siphoviridae are a family of double-stranded DNA Viruses infecting only bacteria that are characterized by a long non-contractile The Podoviridae are a family of Bacteriophages including the following genera Genus T7-like viruses; type species The Corticovirus or Corticoviridae are a family of Phages that consist of a round Icosahedral, non-enveloped Capsid of a diameter of 60 The Lipothrixviridae or Lipothrixvirus family consists of a family of viruses that infect Archaea Bacteria. The Plasmavirus is a family of Bacteriophages viruses that infects bacteria The Rudivirus or Rudiviridae family consists of a family of viruses that infect Archaea Bacteria. Fusellovirus is a genus of DsDNA Virus, which infect the Archaea genus Sulfolobus. The Inoviridae are a family of Bacteriophages including the following genera Genus Inovirus; type species Enterobacteria The Microviridae are a family of Bacteriophages including the following genera Genus Microvirus; type species Enterobacteria The Leviviridae are a family of Viruses including the following genera Genus Levivirus; type species Enterobacteria Cystovirus is a genus of DsRNA Virus, which infect certain Gram negative Bacteria. Leprosy (from the Greek lepi (λέπι meaning scales on a fish or Hansen's disease, is a chronic disease caused by the bacterium In 1896, Ernest Hanbury Hankin reported that something in the waters of the Ganges and Jumna rivers in India had marked antibacterial action against cholera and could pass through a very fine porcelain filter. Ernest Hanbury Hankin (February 4 1865- March 29 1939 was a British bacteriologist aeronautical theorist and naturalist The Ganges (ˈgænʤiːz also Ganga, Devanāgarī: hi गंगा in most Indian languages) is the major river in the Indian subcontinent For the goddess of the river who is sometimes called Yamuna see Yami The Yamuna (Sanskrit यमुना India, officially the Republic of India (भारत गणराज्य inc-Latn Bhārat Gaṇarājya; see also other Indian languages) is a country Antiseptics (from Greek αντί - anti, '"against" + σηπτικός - septikos, "putrefactive" are antimicrobial Cholera, sometimes known as Asiatic cholera or epidemic cholera, is an infectious Gastroenteritis caused by the Bacterium In 1915, British bacteriologist Frederick Twort, superintendent of the Brown Institution of London, discovered a small agent that infected and killed bacteria. The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located Microbiology (from Greek grc μῑκρος mīkros, "small" grc βίος bios, " Life " and grc -λογία Frederick William Twort (1877-1950 was an English Bacteriologist. He considered the agent either 1) a stage in the life cycle of the bacteria, 2) an enzyme produced by the bacteria themselves or 3) a virus that grew on and destroyed the bacteria. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Twort's work was interrupted by the onset of World War I and shortage of funding. World War I (abbreviated WWI; also known as the First World War, the Great War, and the War to End All Independently, French-Canadian microbiologist Félix d'Hérelle, working at the Pasteur Institute in Paris, announced on September 3, 1917 that he had discovered "an invisible, antagonistic microbe of the dysentery bacillus". Microbiology (from Greek grc μῑκρος mīkros, "small" grc βίος bios, " Life " and grc -λογία Félix d'Herelle ( April 25, 1873 &ndash February 22, 1949) was a French-Canadian microbiologist, the co-discoverer of The Pasteur Institute (Institut Pasteur is a French Non-profit private foundation dedicated to the study of Biology, Micro-organisms Diseases Paris (ˈpærɨs in English; in French) is the Capital of France and the country's largest city Events 36 BC - In the Battle of Naulochus, Marcus Vipsanius Agrippa, Admiral of Octavian, defeats Sextus Pompeius Year 1917 ( MCMXVII) was a Common year starting on Monday (link will display the full calendar of the Gregorian calendar (or a Common year Dysentery (formerly known as flux or the bloody flux) is an infection of the digestive system that results in severe Diarrhea containing mucus and blood 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. In 1926 in the Pulitzer-prizewinning novel Arrowsmith, Sinclair Lewis fictionalized the application of bacteriophages as a therapeutic agent. Arrowsmith is a Novel by American Author and Playwright Sinclair Lewis that was published in 1925 Also in the 1920s the Eliava Institute was opened in Tbilisi, Georgia to research this new science and put it into practice. The Tbilisi Institute, now called the George Eliava Institute of Bacteriophage Microbiology and Virology (IBMV has been active since the 1930s in the field of Phage therapy Tbilisi (ˌtbiˈliːsi in Georgian: თბილისი is the capital and the largest city of the Republic of Georgia, lying on the banks of the Mt'k'vari In 2006 the UK Ministry of Defence took responsibility for a G8-funded Global Partnership Priority Eliava Project as a retrospective study to explore the potential of bacteriophages for the 21st century.

Replication

Bacteriophages may have a lytic cycle or a lysogenic cycle, but a few viruses are capable of carrying out both. lytic cycle is one of the two cycles of viral Reproduction, the other being the Lysogenic cycle. Lysogeny, or the lysogenic cycle, is one of two methods of viral reproduction (the Lytic cycle is the other With lytic phages such as the T4 phage, bacterial cells are broken open (lysed) and destroyed after immediate replication of the virion. Enterobacteria phage T4 is a Phage that infects E coli bacteria. As soon as the cell is destroyed, the new bacteriophages viruses can find new hosts. Lytic phages are the kind suitable for phage therapy.

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 fairly harmlessly, or may even become established as a plasmid. A plasmid is an extra-chromosomal DNA molecule separate from the chromosomal DNA which is capable of replicating independently of the chromosomal DNA The virus remains dormant until host conditions deteriorate, perhaps due to depletion of nutrients, then the endogenous phages (known as prophages) become active. The word endogenous means "arising from within" the opposite of Exogenous. 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 reproduced in all of the cell’s offspring.

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. In classical genetics the genome of a Diploid Organism including Eukarya refers to a full set of chromosomes or genes in a Gamete, thereby Lysogeny, or the lysogenic cycle, is one of two methods of viral reproduction (the Lytic cycle is the other A famous example is the conversion of a harmless strain of Vibrio cholerae by a phage into a highly virulent one, which causes cholera. Vibrio cholerae (also Kommabacillus) is a Gram negative curved-rod shaped Bacterium with a polar Flagella that causes Cholera Cholera, sometimes known as Asiatic cholera or epidemic cholera, is an infectious Gastroenteritis caused by the Bacterium This is why temperate phages are not suitable for phage therapy.

Attachment and penetration

A colored electron micrograph of multiple bacteriophages

An electron micrograph of bacteriophages attached to a bacterial cell. A micrograph, microphotograph or photomicrograph is a Photograph or similar image taken through a Microscope or similar device to show A micrograph, microphotograph or photomicrograph is a Photograph or similar image taken through a Microscope or similar device to show These 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. Lipopolysaccharides ( LPS) are large Molecules consisting of a Lipid and a Polysaccharide joined by a Covalent bond; they are found Teichoic acids ( cf Greek τειχος teichos "wall" are polymers of glycerol phosphate or ribitol phospate linked via Phosphodiester bonds Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl A flagellum ( plural flagella) is a tail-like structure that projects from the Cell body of certain Prokaryotic and Eukaryotic cells and it This specificity means that a bacteriophage can only infect certain bacteria bearing receptors that they can bind to, which in turn determines the phage's host range. 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. ).

Complex bacteriophages use a syringe-like motion to inject their genetic material into the cell. A virus (from the Latin virus meaning Toxin or Poison) is a sub-microscopic infectious agent that is unable After making contact with the appropriate receptor, the tail fibers bring the base plate closer to the surface of the cell. Once attached completely, the tail contracts, possibly with the help of ATP present in the tail (Prescott, 1993), injecting genetic material through the bacterial membrane. Adenosine-5'-triphosphate ( ATP) is a multifunctional Nucleotide that is most important as a " molecular currency" of intracellular Energy

Synthesis of proteins and nucleic acid

Within minutes, bacterial ribosomes start translating viral mRNA into protein. Ribosomes ( from ribo nucleic acid and "Greek soma ( meaning body") are complexes of RNA and Protein that For RNA-based phages, RNA replicase is synthesized early in the process. RNA-dependent RNA polymerase ( RDRP) or RNA replicase, is an Enzyme that catalyzes the replication of RNA from an RNA template Proteins modify the bacterial RNA polymerase so that it preferentially transcribes viral mRNA. RNA polymerase ( RNAP or RNApol) is an Enzyme that produces RNA. 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 which help assemble the new virions, or proteins involved in cell lysis. Lysis ( Greek, lysis from lyein = to separate refers to the death of a cell by breaking of the cellular membrane often by viral or osmotic Walter Fiers (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). Walter Fiers (b Ieper, Belgium, 1931 is a Belgian molecular biologist Ghent University (in Dutch Universiteit Gent, abbreviated UGent) is one of the three large Flemish universities. The Kingdom of Belgium is a Country in northwest Europe. It is a founding member of the European Union and hosts its headquarters as well as those The bacteriophage MS2. MS2 phage is an icosahedral bacteriophage with a diameter of 27-34nm and an isoelectric point (pI of 3 ^[5]

Virion assembly

In the case of the T4 phage, the construction of new virus particles involves the assistance of helper proteins. Enterobacteria phage T4 is a Phage that infects E coli bacteria. The base plates are assembled first, with the tails being built upon them afterwards. 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 bacteriophage structure

Release of virions

Phages may be released via cell lysis or by host cell secretion. In the case of the T4 phage, in just over twenty minutes after injection upwards of three hundred phages will be released via lysis within a certain timescale. Enterobacteria phage T4 is a Phage that infects E coli bacteria. This is achieved by an enzyme called endolysin which attacks and breaks down the peptidoglycan. Endolysin is a generic term describing an enzyme that lyses a bacterial membrane Not to be confused with Glycoprotein. Peptidoglycan, also known as murein, is a Polymer consisting of sugars and amino In contrast, "lysogenic" phages do not kill the host but rather become long-term parasites and make the host cell continually secrete more new virus particles. Lysogeny, or the lysogenic cycle, is one of two methods of viral reproduction (the Lytic cycle is the other Parasitism is a type of symbiotic relationship between Organisms of different Species. The new virions bud off the plasma membrane, taking a portion of it with them to become enveloped viruses possessing a viral envelope. A virus (from the Latin virus meaning Toxin or Poison) is a sub-microscopic infectious agent that is unable All released virions are capable of infecting a new bacterium.

Phage therapy

Main article: Phage therapy

Phages were discovered to be anti-bacterial agents and put to use as such soon after they were discovered, with varying success. Phage therapy is the Therapeutic use of Bacteriophages to treat Pathogenic Bacterial infections However, antibiotics were discovered some years later and marketed widely, popular because of their broad spectrum; also easier to manufacture in bulk, store and prescribe. In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa Hence development of phage therapy was largely abandoned in the West, but continued throughout 1940s in the former Soviet Union for treating bacterial infections, with widespread use including the soldiers in the Red Army - much of the literature being in Russian or Georgian, and unavailable for many years in the West. This article refers to the cardinal direction for other uses see West (disambiguation. The 1940s decade ran from 1940 to 1949 Events and trends The 1940s was a period between the radical 1930s and the conservative 1950s which also leads the period to be The Union of Soviet Socialist Republics (USSR was a constitutionally Socialist state that existed in Eurasia from 1922 to 1991 This has continued after the war, with widespread use continuing in Georgia and elsewhere in Eastern Europe. Georgia ( საქართველო, Sakartvelo) is a Transcontinental country in the Caucasus region situated at the dividing line between There is much anecdotal evidence and case studies; There have also been clinical trials in Poland,

Phase 2 human clinical trials are claimed to be nearing completion in a London hospital with ear infections^[6] , and Phase 1 clinical trials are taking place in Lubbock, Texas in a wound care context.

Bacteriophage in the environment

Some time ago it was detected that phages are much more abundant in the water column of freshwater and marine habitats than previously thought and that they can cause significant mortality of bacterioplankton. Bacterioplankton refers to the bacterial component of the Plankton that drifts in the water column Methods in phage community ecology have been developed to assess phage-induced mortality of bacterioplankton and its role for food web process and biogeochemical cycles, to genetically fingerprint phage communities or populations and estimate viral biodiversity by metagenomics. The field of biogeochemistry involves scientific study of the chemical, physical, geological, and biological processes and reactions Biodiversity is the variation of Life forms within a given Ecosystem, Biome or for the entire Earth. Metagenomics (also Environmental Genomics, Ecogenomics or Community Genomics) is the study of genetic material recovered directly from environmental The release of lysis products by phages converts organic carbon from particulate (cells) to dissolved forms (lysis products), which makes organic carbon more bio-available and thus acts as a catalyst of geochemical nutrient cycles. Lysis ( Greek, lysis from lyein = to separate refers to the death of a cell by breaking of the cellular membrane often by viral or osmotic Phages are not only the most abundant biological entities but probably also the most diverse ones. The majority of the sequence data obtained from phage communities has no equivalent in data bases. These data and other detailed analyses indicate that phage-specific genes and ecological traits are much more frequent than previously thought. In order to reveal the meaning of this genetic and ecological versatility, studies have to be performed with communities and at spatiotemporal scales relevant for microorganisms. ^[1]

Bacteriophages have also been used in hydrological tracing and modelling in river systems especially where surface water and groundwater interactions occur. Hydrology (from Greek Yδωρ hudōr, "water" and λόγος logos, "study" is the study of the movement distribution and quality of "Riverine" redirects here For the use of that term in Maritime geography, see there Groundwater is Water located beneath the Ground surface in Soil pore spaces and in the Fractures of lithologic formations The use of phage is preferred to the more conventional dye marker because they are significantly less adsorbed when passing through ground-waters and they are readily detected at very low concentrations. A dye can generally be described as a Colored substance that has an affinity to the substrate to which it is being applied ^[7]

Bacteriophages and food fermentation

A broad number of food products, commodity chemicals, and biotechnology products are manufactured industrially by large-scale bacterial fermentation of various organic substrates. Biotechnology is Technology based on Biology, especially when used in Agriculture, Food science, and Medicine. Because enormous amounts of bacteria are being cultivated each day in large fermentation vats, the risk that bacteriophage contamination rapidly brings fermentations to a halt and cause economical setbacks is a serious threat in these industries. Pollution is the introduction of contaminants into an environment that causes instability disorder harm or discomfort to the physical systems or living organisms they are in The relationship between bacteriophages and their bacterial hosts is very important in the context of the food fermentation industry. Sources of phage contamination, measures to control their propagation and dissemination, and biotechnological defense strategies developed to restrain phages are of interest. The dairy fermentation industry has openly acknowledged the problem of phage and has been working with academia and starter culture companies to develop defense strategies and systems to curtail the propagation and evolution of phages for decades. ^[1]

Other areas of use

In August, 2006 the United States Food and Drug Administration (FDA) approved using bacteriophages on cheese to kill the Listeria monocytogenes bacteria, giving them GRAS status (Generally Recognized As Safe). Listeria monocytogenes is a Gram-positive Bacterium, in the division Firmicutes, named for Joseph Lister. [1] In July 2007, the same bacteriophages were approved for use on all food products. [2]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 e. g. Anthrax, Botulism. There are many developments with this amongst 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 a biocide for environmental surfaces e. g. hospitals - and as a preventative treatment for catheters and medical devices prior to use in clinical settings. The technology now exists for phages to be applied to dry surfaces e. g. uniforms, curtains - even sutures for surgery. Clinical trials reported in the Lancet show success in veterinary treatment of pet dogs with otitis. Phage display is a different use of phages. Phage display is a method for the study of protein-protein protein-peptide and protein-DNA interactions that utilizes Bacteriophage to connect proteins with the genetic information It is a powerful yet simple technique 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 re-infecting a susceptible bacterial strain, thus allowing them to retrieve the peptides encoded in them for further study.

Model bacteriophages

Following is a list of bacteriophages that are extensively studied:

• λ phage - Lysogen
• T2 phage
• T4 phage (169 to 170 kbp, 200 nm long)
• T7 phage
• T12 phage
• R17 phage
• M13 phage
• MS2 phage (23-25 nm in size)
• G4 phage
• P1 phage
• P2 phage
• Phi X 174 phage
• N4 phage
• Φ6 phage
• Φ29 phage
• 186 phage

References

External links

• Häusler, T. (2006) "Viruses vs. Superbugs", Macmillan
• Phage.org general information on bacteriophages
  • Felix d'Hérelle Reference Center for Bacterial Viruses
• August 2007 news article from the BBC
• http://www.npr.org/templates/story/story.php?storyId=1079784
• BBC Horizon (1997): The Virus that Cures - Documentary about the history of phage medicine in Russia and the West
• NPR Science Friday podcast, "Using 'Phage' Viruses to Help Fight Infection", April 2008
• Institute of Immunology and Experimental Therapy

See also

• RNA viruses
• DNA viruses
• Phage ecology
• Phage monographs (a comprehensive listing of phage and phage-associated monographs, 1921-present)
• Phage scientific meetings