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{{Short description|Virus that infects and replicates within bacteria}}{{cs1 config|name-list-style=vanc|display-authors=6}}{{Redirect|Phage}}{{Use dmy dates|date=December 2019}}File:T4 Bacteriophage.gif|thumb|Structural model at atomic resolution of bacteriophage T4JOURNAL, Padilla-Sanchez V, 2021, Structural Model of Bacteriophage T4,en.wikiversity.org/wiki/WikiJournal_of_Science/Structural_Model_of_Bacteriophage_T4, WikiJournal of Science, 4, 1, 5, 10.15347/WJS/2021.005, free, 238939621, ]]File:PhageExterior.svg|right|thumb|The structure of a typical myovirus bacteriophage]]File:11 Hegasy Phage T4 Wiki E CCBYSA.png|thumb|Anatomy and infection cycle of bacteriophage T4.]]A bacteriophage ({{IPAc-en|b|æ|k|ˈ|t|ɪər|i|əʊ|f|eɪ|dÊ’}}), also known informally as a phage ({{IPAc-en|’|f|eɪ|dÊ’}}), is a virus that infects and replicates within bacteria and archaea. The term was derived from “bacteria” and the Greek {{wikt-lang|grc|φαγεῖν}} (), meaning “to devour”. Bacteriophages are composed of proteins that encapsulate a DNA or RNA genome, and may have structures that are either simple or elaborate. Their genomes may encode as few as four genes (e.g. MS2) 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.BOOK, McGrath S, van Sinderen D, Bacteriophage: Genetics and Molecular Biology, 1st, Caister Academic Press, 2007,www.horizonpress.com/phage, 978-1-904455-14-1, 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.NEWS, LaFee S, Buschman H, 25 April 2017,health.ucsd.edu/news/releases/Pages/2017-04-25-novel-phage-therapy-saves-patient-with-multidrug-resistant-bacterial-infection.aspx, Novel Phage Therapy Saves Patient with Multidrug-Resistant Bacterial Infection, UC Health – UC San Diego, 13 May 2018, Viruses are the most abundant biological entity in the water column of the world’s oceans, and the second largest component of biomass after prokaryotes,JOURNAL, Suttle CA, Viruses in the sea, Nature, 437, 7057, 356–361, September 2005, 16163346, 10.1038/nature04160, 4370363, 2005Natur.437..356S, where up to 9x108 virions per millilitre have been found in microbial mats at the surface,JOURNAL, Wommack KE, Colwell RR, Virioplankton: viruses in aquatic ecosystems, Microbiology and Molecular Biology Reviews, 64, 1, 69–114, March 2000, 10704475, 98987, 10.1128/MMBR.64.1.69-114.2000, and up to 70% of marine bacteria may be infected by bacteriophages.BOOK, m Prescott L, 1993, Microbiology, Wm. C. Brown Publishers, 0-697-01372-3, Bacteriophages were used from the 1920s as an alternative to antibiotics in the former Soviet Union and Central Europe, as well as in France.WEB, Bunting J, BBC Worldwide Ltd., BBC Horizon, 1997,archive.org/details/BBCHorizonS1997e13TheVirusThatCures, The Virus that Cures, 224991186, – Documentary about the history of phage medicine in Russia and the WestMAGAZINE, Science talk: Phage factor, Scientific American, August 2012, Borrell B, Fishchetti V, 80–83, 26016042, They are seen as a possible therapy against multi-drug-resistant strains of many bacteria (see phage therapy).JOURNAL, Kortright KE, Chan BK, Koff JL, Turner PE, Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria, Cell Host & Microbe, 25, 2, 219–232, February 2019, 30763536, 10.1016/j.chom.2019.01.014, 73439131, free, JOURNAL, Gordillo Altamirano FL, Barr JJ, Phage Therapy in the Postantibiotic Era, EN, Clinical Microbiology Reviews, 32, 2, April 2019, 30651225, 6431132, 10.1128/CMR.00066-18, JOURNAL, González-Mora A, Hernández-Pérez J, Iqbal HM, Rito-Palomares M, Benavides J, Bacteriophage-Based Vaccines: A Potent Approach for Antigen Delivery, Vaccines, 8, 3, 504, September 2020, 32899720, 7565293, 10.3390/vaccines8030504, free, JOURNAL, Keen EC, Phage therapy: concept to cure, Frontiers in Microbiology, 3, 238, 2012, 22833738, 3400130, 10.3389/fmicb.2012.00238, free, Bacteriophages are known to interact with the immune system both indirectly via bacterial expression of phage-encoded proteins and directly by influencing innate immunity and bacterial clearance. Phage–host interactions are becoming increasingly important areas of research.JOURNAL, Stone E, Campbell K, Grant I, McAuliffe O, Understanding and Exploiting Phage-Host Interactions, Viruses, 11, 6, 567, June 2019, 31216787, 6630733, 10.3390/v11060567, free,

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.File:Bacteriophage P22 Casjens Lenk.png|thumb|right|Bacteriophage P22, a member of the PodoviridaePodoviridaeFile:Enterobacteria phage T2 transmission electron micrograph.jpg|thumb|Bacteriophage T2, a member of the MyoviridaeMyoviridae{| class=“wikitable sortable“|+ ICTV classification of prokaryotic (bacterial and archaeal) viruses style="background:gray;“!Order !! Family !! Morphology !! Nucleic acid !! Examples| Belfryvirales

Turriviridae >		|

Caudovirales	Ackermannviridae >	Viral envelope>enveloped, contractile tail	Linear dsDNA

Autographiviridae >		|

Chaseviridae >		|

Demerecviridae >		|

Drexlerviridae >		|

Guenliviridae >		|

Herelleviridae >		|

Myoviridae >			T4 phage>T4, Mu phage	, P1 phage>P1, P2

Siphoviridae >			Lambda phage>λ, Bacteriophage T5	, HK97, Enterobacteria phage N15>N15

Podoviridae >			T7 phage>T7, T3 phage	, Bacillus phage phi29>Φ29, P22

Rountreeviridae >		|

Salasmaviridae >		|

Schitoviridae >		|

Zobellviridae >		|

Halopanivirales	Sphaerolipoviridae >		|

Simuloviridae >		|

Matshushitaviridae >		|

| Haloruvirales

Pleolipoviridae >		|

| Kalamavirales

Tectiviridae >		|

Ligamenvirales	Lipothrixviridae >		| Acidianus filamentous virus 1

Rudiviridae >		| Sulfolobus islandicus rod-shaped virus 1

| Mindivirales

Cystoviridae >			Pseudomonas virus phi6>Φ6

Norzivirales	Atkinsviridae >		|

Duinviridae >		|

Fiersviridae >			Bacteriophage MS2>MS2, Qβ

Solspiviridae >		|

| Petitvirales

Microviridae >			Phi X 174>ΦX174

| Primavirales

Tristromaviridae >		|

Timlovirales	Blumeviridae >		|

Steitzviridae >		|

Tubulavirales	Inoviridae >			M13 bacteriophage>M13

Paulinoviridae >		|

Plectroviridae >	| Circular ssDNA

| Vinavirales

Corticoviridae >			Pseudoalteromonas virus PM2>PM2

| Durnavirales

Picobirnaviridae (proposal) >		|

Unassigned	Ampullaviridae >		|

Autolykiviridae >		|

Bicaudaviridae >		|

Clavaviridae >		|

Finnlakeviridae >			Flavobacterium virus FLiP>FLiPLAANTO E, MäNTYNEN S, DE COLIBUS L, MARJAKANGAS J, GILLUM A, STUART DI, RAVANTTI JJ, HUISKONEN JT, SUNDBERG LR > TITLE = VIRUS FOUND IN A BOREAL LAKE LINKS SSDNA AND DSDNA VIRUSES	VOLUME = 114	PAGES = 8378–8383	PMID = 28716906	DOI = 10.1073/PNAS.1703834114	BIBCODE = 2017PNAS..114.8378L,

Fuselloviridae >		| Alphafusellovirus

Globuloviridae >		|

Guttaviridae >		|

Halspiviridae >		|

Plasmaviridae >		|

Portogloboviridae >		|

Thaspiviridae >		|

Spiraviridae >		|

It has been suggested that members of Picobirnaviridae infect bacteria, but not mammals.JOURNAL, Krishnamurthy SR, Wang D, Extensive conservation of prokaryotic ribosomal binding sites in known and novel picobirnaviruses, Virology, 516, 108–114, March 2018, 29346073, 10.1016/j.virol.2018.01.006, free, There are also many unassigned genera of the class Leviviricetes: Chimpavirus, Hohglivirus, Mahrahvirus, Meihzavirus, Nicedsevirus, Sculuvirus, Skrubnovirus, Tetipavirus and Winunavirus containing linear ssRNA genomesJOURNAL, Callanan J, Stockdale SR, Adriaenssens EM, Kuhn JH, January 2021, Rename one class (Leviviricetes - formerly Allassoviricetes), rename one order (Norzivirales - formerly Levivirales), create one new order (Timlovirales), and expand the class to a total of six families, 420 genera and 883 species.,www.researchgate.net/publication/349325033, ResearchGate, 10.13140/RG.2.2.25363.40481, and the unassigned genus Lilyvirus of the order Caudovirales containing a linear dsDNA genome.

History

File:Félix d’Hérelle.jpg|right|thumb|upright|Félix d’HerelleFélix d’HerelleIn 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.JOURNAL, Hankin EH, L’action bactericide des eaux de la Jumna et du Gange sur le vibrion du cholera, Annales de l’Institut Pasteur, 1896, 10, 511–23, fr,archive.org/stream/annalesdelinstit10inst#page/511/mode/1up, 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:

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 bacteriaJOURNAL, Twort FW, An Investigation on the Nature of Ultra-Microscopic Viruses, 10.1016/S0140-6736(01)20383-3, The Lancet, 186, 4814, 1241–43, 1915,zenodo.org/record/2380119,

Twort’s research was interrupted by the onset of World War I, as well as a shortage of funding and the discoveries of antibiotics.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.“JOURNAL, d’Hérelles F, 1917, Sur un microbe invisible antagoniste des bacilles dysentériques, Comptes Rendus de l’Académie des Sciences de Paris, 165, 373–5,202.114.65.51/fzjx/wsw/wswfzjs/pdf/1917p157.pdf,202.114.65.51/fzjx/wsw/wswfzjs/pdf/1917p157.pdf," title="web.archive.org/web/20110511183504202.114.65.51/fzjx/wsw/wswfzjs/pdf/1917p157.pdf,">web.archive.org/web/20110511183504202.114.65.51/fzjx/wsw/wswfzjs/pdf/1917p157.pdf, 11 May 2011, 5 September 2010, live, D’Hérelle called the virus a bacteriophage, a bacteria-eater (from the Greek , meaning “to devour“). He also recorded a dramatic account of a man suffering from dysentery who was restored to good health by the bacteriophages.JOURNAL, d’Hérelles F, 1949, The bacteriophage, Science News, 14, 44–59,mmbr.asm.org/cgi/reprint/40/4/793.pdf, 5 September 2010, It was d’Hérelle who conducted much research into bacteriophages and introduced the concept of phage therapy.JOURNAL, Keen EC, Felix d’Herelle and our microbial future, Future Microbiology, 7, 12, 1337–1339, December 2012, 23231482, 10.2217/fmb.12.115, In 1919, in Paris, France, d’Hérelle conducted the first clinical application of a bacteriophage, with the first reported use in the United States being in 1922.JOURNAL, Aswani VH, Shukla SK, An Early History of Phage Therapy in the United States: Is it Time to Reconsider?, Clinical Medicine & Research, 19, 2, 82–89, June 2021, 34172535, 8231696, 10.3121/cmr.2021.1605,

Nobel prizes awarded for phage research

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.WEB,nobelprize.org/nobel_prizes/medicine/laureates/1969/, The Nobel Prize in Physiology or Medicine 1969, 28 July 2007, Nobel Foundation, Specifically the work of Hershey, as contributor to the Hershey–Chase experiment in 1952, provided convincing evidence that DNA, not protein, was the genetic material of life. Delbrück and Luria carried out the Luria–Delbrück experiment which demonstrated statistically that mutations in bacteria occur randomly and thus follow Darwinian rather than Lamarckian principles.

Uses

Phage therapy

File:George Eliava 1892–1937.jpg|right|thumb|upright|George EliavaGeorge EliavaPhages 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’Hérelle) during the 1920s and 1930s for treating bacterial infections. 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.“{{Citation | vauthors = Kuchment A | year = 2012 | title = The Forgotten Cure: The past and future of phage therapy | publisher = Springer | page = 11 | isbn = 978-1-4614-0250-3 }} They had widespread use, including treatment of soldiers in the Red Army.JOURNAL, Myelnikov D, An Alternative Cure: The Adoption and Survival of Bacteriophage Therapy in the USSR, 1922-1955, Journal of the History of Medicine and Allied Sciences, 73, 4, 385–411, October 2018, 30312428, 6203130, 10.1093/jhmas/jry024, 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 prescribe.
• Medical trials of phages were carried out, but a basic lack of understanding of phages raised questions about the validity of these trials.JOURNAL, Kutter E, De Vos D, Gvasalia G, Alavidze Z, Gogokhia L, Kuhl S, Abedon ST, Phage therapy in clinical practice: treatment of human infections, Current Pharmaceutical Biotechnology, 11, 1, 69–86, January 2010, 20214609, 10.2174/138920110790725401, 31626252,
• 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,JOURNAL, Golovin S,www.nkj.ru/archive/articles/31498/, Бактериофаги: убийцы в роли спасителей, Bacteriophages: killers as saviors, Russian, Наука и жизнь, Nauka I Zhizn (Science and life), 2017, 6, 26–33, 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.JOURNAL, Rhoads DD, Wolcott RD, Kuskowski MA, Wolcott BM, Ward LS, Sulakvelidze A, Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial, Journal of Wound Care, 18, 6, 237–8, 240–3, June 2009, 19661847, 10.12968/jowc.2009.18.6.42801, 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. 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.JOURNAL, Wright A, Hawkins CH, AnggÃ¥rd EE, Harper DR, A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy, Clinical Otolaryngology, 34, 4, 349–357, August 2009, 19673983, 10.1111/j.1749-4486.2009.01973.x, free, 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. On the other hand, 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.JOURNAL, Sweere JM, Van Belleghem JD, Ishak H, Bach MS, Popescu M, Sunkari V, Kaber G, Manasherob R, Suh GA, Cao X, de Vries CR, Lam DN, Marshall PL, Birukova M, Katznelson E, Lazzareschi DV, Balaji S, Keswani SG, Hawn TR, Secor PR, Bollyky PL, Bacteriophage trigger antiviral immunity and prevent clearance of bacterial infection, Science, 363, 6434, eaat9691, March 2019, 30923196, 6656896, 10.1126/science.aat9691, free, 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. 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.JOURNAL, Tawil N, Sacher E, Mandeville R, Meunier M, Surface plasmon resonance detection of E. coli and methicillin-resistant S. aureus using bacteriophages, Biosensors & Bioelectronics, 37, 1, 24–29, May 2012, 22609555, 10.1016/j.bios.2012.04.048,lp2l.polymtl.ca/sites/default/files/Articles/2012-Tawil.pdf, live,web.archive.org/web/20230202231339/https://lp2l.polymtl.ca/sites/default/files/Articles/2012-Tawil.pdf, 2023-02-02, Therapeutic efficacy of a phage cocktail was evaluated in a mouse model with nasal infection of multi-drug-resistant (MDR) A. baumannii. Mice treated with the phage cocktail showed a 2.3-fold higher survival rate compared to those untreated at seven days post-infection.JOURNAL, Cha K, Oh HK, Jang JY, Jo Y, Kim WK, Ha GU, Ko KS, Myung H, Characterization of Two Novel Bacteriophages Infecting Multidrug-Resistant (MDR) Acinetobacter baumannii and Evaluation of Their Therapeutic Efficacy in Vivo, Frontiers in Microbiology, 9, 696, 10 April 2018, 29755420, 5932359, 10.3389/fmicb.2018.00696, free, In 2017, a 68-year-old diabetic patient with necrotizing pancreatitis complicated by a pseudocyst infected with MDR A. baumannii strains was being treated with a cocktail of Azithromycin, Rifampicin, and Colistin for 4 months without results and overall rapidly declining health. Because discussion had begun of the clinical futility of further treatment, an Emergency Investigational New Drug (eIND) was filed as a last effort to at the very least gain valuable medical data from the situation, and approved, so he was subjected to phage therapy using a percutaneously (PC) injected cocktail containing nine different phages that had been identified as effective against the primary infection strain by rapid isolation and testing techniques (a process which took under a day). This proved effective for a very brief period, although the patient remained unresponsive and his health continued to worsen; soon isolates of a strain of A. baumannii were being collected from drainage of the cyst that showed resistance to this cocktail, and a second cocktail which was tested to be effective against this new strain was added, this time by intravenous (IV) injection as it had become clear that the infection was more pervasive than originally thought. Once on the combination of the IV and PC therapy the patient’s downward clinical trajectory reversed, and within two days he had awoken from his coma and become responsive. As his immune system began to function he had to be temporarily removed from the cocktail because his fever was spiking to over {{convert|104|F|C}}, but after two days the phage cocktails were re-introduced at levels he was able to tolerate. The original three-antibiotic cocktail was replaced by minocycline after the bacterial strain was found not to be resistant to this and he rapidly regained full lucidity, although he was not discharged from the hospital until roughly 145 days after phage therapy began. Towards the end of the therapy it was discovered that the bacteria had become resistant to both of the original phage cocktails, but they were continued because they seemed to be preventing minocycline resistance from developing in the bacterial samples collected so were having a useful synergistic effect. JOURNAL, Schooley RT, Biswas B, Gill JJ, Hernandez-Morales A, Lancaster J, Lessor L, Barr JJ, Reed SL, Rohwer F, Benler S, Segall AM, Taplitz R, Smith DM, Kerr K, Kumaraswamy M, Nizet V, Lin L, McCauley MD, Strathdee SA, Benson CA, Pope RK, Leroux BM, Picel AC, Mateczun AJ, Cilwa KE, Regeimbal JM, Estrella LA, Wolfe DM, Henry MS, Quinones J, Salka S, Bishop-Lilly KA, Young R, Hamilton T, Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection, Antimicrobial Agents and Chemotherapy, 61, 10, October 2017, 28807909, 5610518, 10.1128/AAC.00954-17,

Other

Food industry

Phages have increasingly been used to safen food products and to forestall spoilage bacteria.JOURNAL, O’Sullivan L, Bolton D, McAuliffe O, Coffey A, Bacteriophages in Food Applications: From Foe to Friend, Annual Review of Food Science and Technology, 10, 1, 151–172, March 2019, 30633564, 10.1146/annurev-food-032818-121747, Annual Reviews (publisher), Annual Reviews, 58620015, 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.U.S. FDA/CFSAN: Agency Response Letter, GRAS Notice No. 000198 In July 2007, the same bacteriophage were approved for use on all food products.(U.S. FDA/CFSAN: Agency Response Letter, GRAS Notice No. 000218) In 2011 USDA confirmed that LISTEX is a clean label processing aid and is included in USDA.WEB,www.fsis.usda.gov/oppde/rdad/fsisdirectives/7120.1.pdf, FSIS Directive 7120: Safe and Suitable Ingredients Used in the Production of Meat, Poultry, and Egg Products, United States Department of Agriculture, Food Safety and Inspection Service, Washington, DC,www.fsis.usda.gov/OPPDE/rdad/FSISDirectives/7120.1.pdf," title="web.archive.org/web/20111018071043www.fsis.usda.gov/OPPDE/rdad/FSISDirectives/7120.1.pdf,">web.archive.org/web/20111018071043www.fsis.usda.gov/OPPDE/rdad/FSISDirectives/7120.1.pdf, 18 October 2011, 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.JOURNAL, Khan FM, Chen JH, Zhang R, Liu B, A comprehensive review of the applications of bacteriophage-derived endolysins for foodborne bacterial pathogens and food safety: recent advances, challenges, and future perspective, Frontiers in Microbiology, 14, 1259210, 2023, 37869651, 10588457, 10.3389/fmicb.2023.1259210, free,

Water indicators

Bacteriophages, including those specific to Escherichia coli, have been employed as indicators of fecal contamination in water sources. Due to their shared structural and biological characteristics, coliphages can serve as proxies for viral fecal contamination and the presence of pathogenic viruses such as rotavirus, norovirus, and HAV. Research conducted on wastewater treatment systems has revealed significant disparities in the behavior of coliphages compared to fecal coliforms, demonstrating a distinct correlation with the recovery of pathogenic viruses at the treatment’s conclusion. Establishing a secure discharge threshold, studies have determined that discharges below 3000 PFU/100 mL are considered safe in terms of limiting the release of pathogenic viruses. Chacón L, Barrantes K, Santamaría-Ulloa C, Solano MReyes L, Taylor LValiente C, Symonds EM, Achí R. 2020. A Somatic Coliphage Threshold Approach To Improve the Management of Activated Sludge Wastewater Treatment Plant Effluents in Resource-Limited Regions. Appl Environ Microbiol 86:e00616-20doi.org/10.1128/AEM.00616-20/

Diagnostics

In 2011, the FDA cleared the first bacteriophage-based product for in vitro diagnostic use.WEB,www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K102342, FDA 510(k) Premarket Notification, U.S. Food and Drug Administration, 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.JOURNAL,www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254512.htm, FDA clears first test to quickly diagnose and distinguish MRSA and MSSA, U.S. Food and Drug Administration, 6 May 2011, 10.1128/aem.00616-20, 32591380,journals.asm.org/doi/10.1128/aem.00616-20, 5 April 2024, Applied and Environmental Microbiology, 86, 17, 7440787, Chacón L, Barrantes K, Santamaría-Ulloa C, Solano M, Reyes L, Taylor L, Valiente C, Symonds EM, Achí R,

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.WEB, Vaisman D, 25 May 2007,www.nytimes.com/2007/05/25/world/americas/25iht-institute.4.5869943.html, Studying anthrax in a Soviet-era lab – with Western funding, The New York Times, 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 show success in veterinary treatment of pet dogs with otitis.

Bacterium sensing and identification

The sensing of phage-triggered ion cascades (SEPTIC) bacterium sensing and identification method uses the ion emission and its dynamics during phage infection and offers high specificity and speed for detection.JOURNAL,www.ece.tamu.edu/%7Enoise/research_files/King_et_al_JBPC.pdf, Dobozi-King M, Seo S, Kim JU, Young R, Cheng M, Kish LB, Rapid detection and identification of bacteria: SEnsing of Phage-Triggered Ion Cascade (SEPTIC), Journal of Biological Physics and Chemistry, 5, 2005, 3–7, 10.4024/1050501.jbpc.05.01, 19 December 2016, 26 September 2018,www.ece.tamu.edu/%7Enoise/research_files/King_et_al_JBPC.pdf," title="web.archive.org/web/20180926123955www.ece.tamu.edu/%7Enoise/research_files/King_et_al_JBPC.pdf,">web.archive.org/web/20180926123955www.ece.tamu.edu/%7Enoise/research_files/King_et_al_JBPC.pdf, dead,

Phage display

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.JOURNAL, Smith GP, Petrenko VA, Phage Display, Chemical Reviews, 97, 2, 391–410, April 1997, 11848876, 10.1021/cr960065d,

Antimicrobial drug discovery

Phage proteins often have antimicrobial activity and may serve as leads for peptidomimetics, i.e. drugs that mimic peptides.JOURNAL, Liu J, Dehbi M, Moeck G, Arhin F, Bauda P, Bergeron D, Callejo M, Ferretti V, Ha N, Kwan T, McCarty J, Srikumar R, Williams D, Wu JJ, Gros P, Pelletier J, DuBow M, Antimicrobial drug discovery through bacteriophage genomics, Nature Biotechnology, 22, 2, 185–191, February 2004, 14716317, 10.1038/nbt932, 9905115, 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.WEB,www.hyglos.de/en/technology/technological-background.html, Technological background Phage-ligand technology, bioMérieux,

Basic research

Bacteriophages are important model organisms for studying principles of evolution and ecology.JOURNAL, Keen EC, Tradeoffs in bacteriophage life histories, Bacteriophage, 4, 1, e28365, January 2014, 24616839, 3942329, 10.4161/bact.28365,

Detriments

Dairy industry

Bacteriophages present in the environment can cause cheese to not ferment. In order to avoid this, mixed-strain starter cultures and culture rotation regimes can be used.JOURNAL, Atamer Z, Samtlebe M, Neve H, J Heller K, Hinrichs J, Review: elimination of bacteriophages in whey and whey products, Frontiers in Microbiology, 4, 191, 16 July 2013, 23882262, 3712493, 10.3389/fmicb.2013.00191, free, Genetic engineering of culture microbes – especially Lactococcus lactis and Streptococcus thermophilus – have been studied for genetic analysis and modification to improve phage resistance. This has especially focused on plasmid and recombinant chromosomal modifications.JOURNAL, Coffey A, Ross RP, Bacteriophage-resistance systems in dairy starter strains: molecular analysis to application, Antonie van Leeuwenhoek, 82, 1–4, 303–321, August 2002, 12369198, 10.1023/a:1020639717181, Springer Science+Business Media, Springer, 7217985, Some research has focused on the potential of bacteriophages as antimicrobial against foodborne pathogens and biofilm formation within the dairy industry. As the spread of antibiotic resistance is a main concern within the dairy industry, phages can serve as a promising alternative.JOURNAL, Fernández L, Escobedo S, Gutiérrez D, Portilla S, Martínez B, García P, Rodríguez A, Bacteriophages in the Dairy Environment: From Enemies to Allies, Antibiotics, 6, 4, 27, November 2017, 29117107, 5745470, 10.3390/antibiotics6040027, [MDPI], free,

Replication

(File:Phage injection.png|thumb|right|upright=2|Diagram of the DNA injection process)The life cycle of bacteriophages tends to be either a lytic cycle or a lysogenic cycle. In addition, some phages display pseudolysogenic behaviors.JOURNAL, Popescu M, Van Belleghem JD, Khosravi A, Bollyky PL, Bacteriophages and the Immune System, Annual Review of Virology, 8, 1, 415–435, September 2021, 34014761, 10.1146/annurev-virology-091919-074551, free, 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 the temperate phage going dormant and usually is temporary.JOURNAL, Abedon ST, Look Who’s Talking: T-Even Phage Lysis Inhibition, the Granddaddy of Virus-Virus Intercellular Communication Research, Viruses, 11, 10, 951, October 2019, 31623057, 6832632, 10.3390/v11100951, free, 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.BOOK, Mason KA, Losos JB, Singer SR, Raven PH, Johnson GB, 2011, Biology, 533, McGraw-Hill, New York, 978-0-07-893649-4, 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.JOURNAL, Mokrousov I, Corynebacterium diphtheriae: genome diversity, population structure and genotyping perspectives, Infection, Genetics and Evolution, 9, 1, 1–15, January 2009, 19007916, 10.1016/j.meegid.2008.09.011, JOURNAL, Charles RC, Ryan ET, Cholera in the 21st century, Current Opinion in Infectious Diseases, 24, 5, 472–477, October 2011, 21799407, 10.1097/QCO.0b013e32834a88af, 6907842, Strategies to combat certain bacterial infections by targeting these toxin-encoding prophages have been proposed.JOURNAL, Keen EC, Paradigms of pathogenesis: targeting the mobile genetic elements of disease, Frontiers in Cellular and Infection Microbiology, 2, 161, December 2012, 23248780, 3522046, 10.3389/fcimb.2012.00161, free,

Attachment and penetration

File:Phage.jpg|thumb|In this electron micrographelectron micrographBacterial cells are protected by a cell wall of polysaccharides, which are important virulence factors protecting bacterial cells against both immune host defenses and antibiotics.JOURNAL, Drulis-Kawa Z, Majkowska-Skrobek G, Maciejewska B, Bacteriophages and phage-derived proteins--application approaches, Current Medicinal Chemistry, 22, 14, 1757–1773, 2015, 25666799, 4468916, 10.2174/0929867322666150209152851, {{citation needed span|date=November 2021|To enter a host cell, bacteriophages bind 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. Polysaccharide-degrading enzymes are virion-associated proteins that enzymatically degrade the capsular outer layer of their hosts at the initial step of a tightly programmed phage infection process.}}Host growth conditions also influence the ability of the phage to attach and invade them.JOURNAL, Gabashvili IS, Khan SA, Hayes SJ, Serwer P, Polymorphism of bacteriophage T7, Journal of Molecular Biology, 273, 3, 658–667, October 1997, 9356254, 10.1006/jmbi.1997.1353, As phage virions do not move independently, they must rely on random encounters with the correct receptors when in solution, such as blood, lymphatic circulation, irrigation, soil water, etc.{{citation needed|date=October 2022}}Myovirus bacteriophages use a hypodermic syringe-like motion to inject their genetic material into the cell. After contacting 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.JOURNAL, Maghsoodi A, Chatterjee A, Andricioaei I, Perkins NC, How the phage T4 injection machinery works including energetics, forces, and dynamic pathway, Proceedings of the National Academy of Sciences of the United States of America, 116, 50, 25097–25105, December 2019, 31767752, 6911207, 10.1073/pnas.1909298116, free, 2019PNAS..11625097M, The injection is accomplished through a sort of bending motion in the shaft by going to the side, contracting closer to the cell and pushing back up. Podoviruses lack an elongated tail sheath like that of a myovirus, so instead, they 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 mRNA into 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 contribute to the assemblage of new virions, or proteins involved in cell lysis. In 1972, Walter Fiers (University of Ghent, Belgium) was the first to establish the complete nucleotide sequence of a gene and in 1976, of the viral genome of bacteriophage MS2.JOURNAL, Fiers W, Contreras R, Duerinck F, Haegeman G, Iserentant D, Merregaert J, Min Jou W, Molemans F, Raeymaekers A, Van den Berghe A, Volckaert G, Ysebaert M, Complete nucleotide sequence of bacteriophage MS2 RNA: primary and secondary structure of the replicase gene, Nature, 260, 5551, 500–507, April 1976, 1264203, 10.1038/260500a0, 4289674, 1976Natur.260..500F, Some dsDNA bacteriophages encode ribosomal proteins, which are thought to modulate protein translation during phage infection.JOURNAL, Mizuno CM, Guyomar C, Roux S, Lavigne R, Rodriguez-Valera F, Sullivan MB, Gillet R, Forterre P, Krupovic M, Numerous cultivated and uncultivated viruses encode ribosomal proteins, Nature Communications, 10, 1, 752, February 2019, 30765709, 6375957, 10.1038/s41467-019-08672-6, 2019NatCo..10..752M,

Virion assembly

In the case of the T4 phage, the construction of new virus particles involves the assistance of helper proteins that act catalytically during phage morphogenesis.JOURNAL, Snustad DP, Dominance interactions in Escherichia coli cells mixedly infected with bacteriophage T4D wild-type and amber mutants and their possible implications as to type of gene-product function: catalytic vs. stoichiometric, Virology, 35, 4, 550–563, August 1968, 4878023, 10.1016/0042-6822(68)90285-7, 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. During assembly of the phage T4 virion, the morphogenetic proteins encoded by the phage genes interact with each other in a characteristic sequence. Maintaining an appropriate balance in the amounts of each of these proteins produced during viral infection appears to be critical for normal phage T4 morphogenesis.JOURNAL, Floor E, Interaction of morphogenetic genes of bacteriophage T4, Journal of Molecular Biology, 47, 3, 293–306, February 1970, 4907266, 10.1016/0022-2836(70)90303-7, The DNA is packed efficiently within the heads.JOURNAL, Petrov AS, Harvey SC, Packaging double-helical DNA into viral capsids: structures, forces, and energetics, Biophysical Journal, 95, 2, 497–502, July 2008, 18487310, 2440449, 10.1529/biophysj.108.131797, 2008BpJ....95..497P, 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, makes 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 and instead become long-term residents as prophages.JOURNAL, Henrot C, Petit MA, Signals triggering prophage induction in the gut microbiota, Molecular Microbiology, 118, 5, 494–502, November 2022, 36164818, 9827884, 10.1111/mmi.14983, 252542284,

Communication

Research in 2017 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.JOURNAL, Callaway E, 10.1038/nature.2017.21313, free,www.nature.com/news/do-you-speak-virus-phages-caught-sending-chemical-messages-1.21313, Do you speak virus? Phages caught sending chemical messages, Nature, 2017, JOURNAL, Erez Z, Steinberger-Levy I, Shamir M, Doron S, Stokar-Avihail A, Peleg Y, Melamed S, Leavitt A, Savidor A, Albeck S, Amitai G, Sorek R, Communication between viruses guides lysis-lysogeny decisions, Nature, 541, 7638, 488–493, January 2017, 28099413, 5378303, 10.1038/nature21049, 2017Natur.541..488E,

Genome structure

Given the millions of different phages in the environment, phage genomes come in a variety of forms and sizes. RNA phages such as MS2 have the smallest genomes, with 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.BOOK, Black LW, Thomas JA, Viral Molecular Machines, Condensed Genome Structure, 2012, 726, 469–87, 22297527, 3559133, 10.1007/978-1-4614-0980-9_21, Advances in Experimental Medicine and Biology, Springer, 978-1-4614-0979-3, The largest bacteriophage genomes reach a size of 735 kb.JOURNAL, Al-Shayeb B, Sachdeva R, Chen LX, Ward F, Munk P, Devoto A, Castelle CJ, Olm MR, Bouma-Gregson K, Amano Y, He C, Méheust R, Brooks B, Thomas A, Lavy A, Matheus-Carnevali P, Sun C, Goltsman DS, Borton MA, Sharrar A, Jaffe AL, Nelson TC, Kantor R, Keren R, Lane KR, Farag IF, Lei S, Finstad K, Amundson R, Anantharaman K, Zhou J, Probst AJ, Power ME, Tringe SG, Li WJ, Wrighton K, Harrison S, Morowitz M, Relman DA, Doudna JA, Lehours AC, Warren L, Cate JH, Santini JM, Banfield JF, Clades of huge phages from across Earth’s ecosystems, Nature, 578, 7795, 425–431, February 2020, 32051592, 7162821, 10.1038/s41586-020-2007-4, free, 2020Natur.578..425A, File:T7 phage genome.png|alt=Phage T7 genome (schematic)|thumb|797x797px|Schematic view of the 44 kb T7 phageT7 phageBacteriophage 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).JOURNAL, Morris P, Marinelli LJ, Jacobs-Sera D, Hendrix RW, Hatfull GF, Genomic characterization of mycobacteriophage Giles: evidence for phage acquisition of host DNA by illegitimate recombination, Journal of Bacteriology, 190, 6, 2172–2182, March 2008, 18178732, 2258872, 10.1128/JB.01657-07, Evolutionary mechanisms shaping the genomes of bacterial viruses vary between different families and depend upon the type of the nucleic acid, characteristics of the virion structure, as well as the mode of the viral life cycle.JOURNAL, Krupovic M, Prangishvili D, Hendrix RW, Bamford DH, Genomics of bacterial and archaeal viruses: dynamics within the prokaryotic virosphere, Microbiology and Molecular Biology Reviews, 75, 4, 610–635, December 2011, 22126996, 3232739, 10.1128/MMBR.00011-11, Some marine roseobacter phages contain deoxyuridine (dU) instead of deoxythymidine (dT) in their genomic DNA. There is some evidence that this unusual component is a mechanism to evade bacterial defense mechanisms such as restriction endonucleases and CRISPR/Cas systems which evolved to recognize and cleave sequences within invading phages, thereby inactivating them. Other phages have long been known to use unusual nucleotides. In 1963, Takahashi and Marmur identified a Bacillus phage that has dU substituting dT in its genome,JOURNAL, Takahashi I, Marmur J, Replacement of thymidylic acid by deoxyuridylic acid in the deoxyribonucleic acid of a transducing phage for Bacillus subtilis, Nature, 197, 4869, 794–795, February 1963, 13980287, 10.1038/197794a0, 4166988, 1963Natur.197..794T, and in 1977, Kirnos et al. identified a cyanophage containing 2-aminoadenine (Z) instead of adenine (A).JOURNAL, Kirnos MD, Khudyakov IY, Alexandrushkina NI, Vanyushin BF, 2-aminoadenine is an adenine substituting for a base in S-2L cyanophage DNA, Nature, 270, 5635, 369–370, November 1977, 413053, 10.1038/270369a0, 4177449, 1977Natur.270..369K,

Systems biology

The field of systems biology investigates the complex networks of interactions within an organism, usually using computational tools and modeling.BOOK,www.worldcat.org/oclc/288986435, Systems biology: a textbook, 2009, Wiley-VCH, Klipp E, 978-3-527-31874-2, Weinheim, 288986435, For example, a phage genome that enters into a bacterial host cell may express hundreds of phage proteins which will affect the expression of numerous host genes or the host’s metabolism. All of these complex interactions can be described and simulated in computer models.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.JOURNAL, Zhao X, Chen C, Shen W, Huang G, Le S, Lu S, Li M, Zhao Y, Wang J, Rao X, Li G, Shen M, Guo K, Yang Y, Tan Y, Hu F, Global Transcriptomic Analysis of Interactions between Pseudomonas aeruginosa and Bacteriophage PaP3, Scientific Reports, 6, 19237, January 2016, 26750429, 4707531, 10.1038/srep19237, 2016NatSR...619237Z, 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 dozens of interactions. 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.JOURNAL, Blasche S, Wuchty S, Rajagopala SV, Uetz P, The protein interaction network of bacteriophage lambda with its host, Escherichia coli, Journal of Virology, 87, 23, 12745–12755, December 2013, 24049175, 3838138, 10.1128/JVI.02495-13,

Host resistance

Bacteriophages are a major threat to bacteria and prokaryotes have evolved numerous mechanisms to block infection or to block the replication of bacteriophages within host cells. The CRISPR system is one such mechanism as are retrons and the anti-toxin system encoded by them.JOURNAL, Bobonis J, Mitosch K, Mateus A, Karcher N, Kritikos G, Selkrig J, Zietek M, Monzon V, Pfalz B, Garcia-Santamarina S, Galardini M, Sueki A, Kobayashi C, Stein F, Bateman A, Zeller G, Savitski MM, Elfenbein JR, Andrews-Polymenis HL, Typas A, Bacterial retrons encode phage-defending tripartite toxin-antitoxin systems, Nature, 609, 7925, 144–150, September 2022, 35850148, 10.1038/s41586-022-05091-4, 250643138, 2022Natur.609..144B, The Thoeris defense system is known to deploy a unique strategy for bacterial antiphage resistance via NAD+ degradation.JOURNAL, Ka D, Oh H, Park E, Kim JH, Bae E, Structural and functional evidence of bacterial antiphage protection by Thoeris defense system via NAD+ degradation, Nature Communications, 11, 1, 2816, June 2020, 32499527, 7272460, 10.1038/s41467-020-16703-w, 2020NatCo..11.2816K,

Bacteriophage–host symbiosis

Temperate phages are bacteriophages that integrate their genetic material into the host as extrachromosomal episomes or as a prophage during a lysogenic cycle.JOURNAL, Cieślik M, Bagińska N, Jończyk-Matysiak E, Węgrzyn A, Węgrzyn G, Górski A, Temperate Bacteriophages-The Powerful Indirect Modulators of Eukaryotic Cells and Immune Functions, Viruses, 13, 6, 1013, May 2021, 34071422, 8228536, 10.3390/v13061013, free, JOURNAL, Wendling CC, Refardt D, Hall AR, Fitness benefits to bacteria of carrying prophages and prophage-encoded antibiotic-resistance genes peak in different environments, Evolution; International Journal of Organic Evolution, 75, 2, 515–528, February 2021, 33347602, 7986917, 10.1111/evo.14153, JOURNAL, Kirsch JM, Brzozowski RS, Faith D, Round JL, Secor PR, Duerkop BA, Bacteriophage-Bacteria Interactions in the Gut: From Invertebrates to Mammals, Annual Review of Virology, 8, 1, 95–113, September 2021, 34255542, 8484061, 10.1146/annurev-virology-091919-101238, Some temperate phages can confer fitness advantages to their host in numerous ways, including giving antibiotic resistance through the transfer or introduction of antibiotic resistance genes (ARGs),JOURNAL, Brenciani A, Bacciaglia A, Vignaroli C, Pugnaloni A, Varaldo PE, Giovanetti E, Phim46.1, the main Streptococcus pyogenes element carrying mef(A) and tet(O) genes, Antimicrobial Agents and Chemotherapy, 54, 1, 221–229, January 2010, 19858262, 2798480, 10.1128/AAC.00499-09, protecting hosts from phagocytosis,JOURNAL, Jahn MT, Arkhipova K, Markert SM, Stigloher C, Lachnit T, Pita L, Kupczok A, Ribes M, Stengel ST, Rosenstiel P, Dutilh BE, Hentschel U, A Phage Protein Aids Bacterial Symbionts in Eukaryote Immune Evasion, Cell Host & Microbe, 26, 4, 542–550.e5, October 2019, 31561965, 10.1016/j.chom.2019.08.019, 203580138, free, JOURNAL, Leigh BA, Cooperation among Conflict: Prophages Protect Bacteria from Phagocytosis, English, Cell Host & Microbe, 26, 4, 450–452, October 2019, 31600498, 10.1016/j.chom.2019.09.003, 204243652, free, protecting hosts from secondary infection through superinfection exclusion,JOURNAL, Ali Y, Koberg S, Heßner S, Sun X, Rabe B, Back A, Neve H, Heller KJ, Temperate Streptococcus thermophilus phages expressing superinfection exclusion proteins of the Ltp type, Frontiers in Microbiology, 5, 98, 2014, 24659988, 3952083, 10.3389/fmicb.2014.00098, free, JOURNAL, McGrath S, Fitzgerald GF, van Sinderen D, Identification and characterization of phage-resistance genes in temperate lactococcal bacteriophages, Molecular Microbiology, 43, 2, 509–520, January 2002, 11985726, 10.1046/j.1365-2958.2002.02763.x, 7084706, free, BOOK, Douwe M, McGrath J, Fitzgerald S, van Sinderen GF,worldcat.org/oclc/679550931, Identification and Characterization of Lactococcal-Prophage-Carried Superinfection Exclusion Genes▿ †, American Society for Microbiology (ASM), 679550931, enhancing host pathogenicity,JOURNAL, Brüssow H, Canchaya C, Hardt WD, Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion, Microbiology and Molecular Biology Reviews, 68, 3, 560–602, table of contents, September 2004, 15353570, 515249, 10.1128/MMBR.68.3.560-602.2004, or enhancing bacterial metabolism or growth.JOURNAL, Edlin G, Lin L, Kudrna R, Lambda lysogens of E. coli reproduce more rapidly than non-lysogens, Nature, 255, 5511, 735–737, June 1975, 1094307, 10.1038/255735a0, 1975Natur.255..735E, 4156346, JOURNAL, Sekulovic O, Fortier LC, Global transcriptional response of Clostridium difficile carrying the CD38 prophage, Applied and Environmental Microbiology, 81, 4, 1364–1374, February 2015, 25501487, 4309704, 10.1128/AEM.03656-14, 2015ApEnM..81.1364S, Schaffner DW, JOURNAL, Rossmann FS, Racek T, Wobser D, Puchalka J, Rabener EM, Reiger M, Hendrickx AP, Diederich AK, Jung K, Klein C, Huebner J, Phage-mediated dispersal of biofilm and distribution of bacterial virulence genes is induced by quorum sensing, PLOS Pathogens, 11, 2, e1004653, February 2015, 25706310, 4338201, 10.1371/journal.ppat.1004653, free, JOURNAL, Obeng N, Pratama AA, Elsas JD, The Significance of Mutualistic Phages for Bacterial Ecology and Evolution, English, Trends in Microbiology, 24, 6, 440–449, June 2016, 26826796, 10.1016/j.tim.2015.12.009, 3565635,pure.rug.nl/ws/files/241447214/1_s2.0_S0966842X15003005_main.pdf, Bacteriophage–host symbiosis may benefit bacteria by providing selective advantages while passively replicating the phage genome.JOURNAL, Li G, Cortez MH, Dushoff J, Weitz JS, When to be temperate: on the fitness benefits of lysis vs. lysogeny, Virus Evolution, 6, 2, veaa042, July 2020, 36204422, 9532926, 10.1093/ve/veaa042, 10.1101/709758,

In the environment

Metagenomics has allowed the in-water detection of bacteriophages that was not possible previously.JOURNAL, Breitbart M, Salamon P, Andresen B, Mahaffy JM, Segall AM, Mead D, Azam F, Rohwer F, Genomic analysis of uncultured marine viral communities, Proceedings of the National Academy of Sciences of the United States of America, 99, 22, 14250–14255, October 2002, 12384570, 137870, 10.1073/pnas.202488399, free, 2002PNAS...9914250B, Mya Breitbart, 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.JOURNAL, Martin C, 10.1111/j.1747-6593.1988.tb01352.x, The Application of Bacteriophage Tracer Techniques in South West Water, Water and Environment Journal, 2, 6, 638–642, 1988, 1988WaEnJ...2..638M, Non-polluted water may contain approximately 2×108 bacteriophages per ml.JOURNAL, Bergh O, Børsheim KY, Bratbak G, Heldal M, High abundance of viruses found in aquatic environments, Nature, 340, 6233, 467–468, August 1989, 2755508, 10.1038/340467a0, 4271861, 1989Natur.340..467B, Bacteriophages are thought to contribute extensively to horizontal gene transfer in natural environments, principally via transduction, but also via transformation.JOURNAL, Keen EC, Bliskovsky VV, Malagon F, Baker JD, Prince JS, Klaus JS, Adhya SL, Novel “Superspreader” Bacteriophages Promote Horizontal Gene Transfer by Transformation, mBio, 8, 1, e02115–16, January 2017, 28096488, 5241400, 10.1128/mBio.02115-16, Metagenomics-based studies also have revealed that viromes from a variety of environments harbor antibiotic-resistance genes, including those that could confer multidrug resistance.JOURNAL, Lekunberri I, Subirats J, Borrego CM, Balcázar JL, Exploring the contribution of bacteriophages to antibiotic resistance, Environmental Pollution, 220, Pt B, 981–984, January 2017, 27890586, 10.1016/j.envpol.2016.11.059, 2017EPoll.220..981L, 10256/14115, Recent findings have mapped the complex and intertwined arsenal of anti-phage defense tools in environmental bacteria.JOURNAL, Beavogui A, Lacroix A, Wiart N, Poulain J, Delmont TO, Paoli L, Wincker P, Oliveira PH, The defensome of complex bacterial communities, Nature Communications, 15, 1, 2146, March 2024, 38459056, 10924106, 10.1038/s41467-024-46489-0, 2024NatCo..15.2146B,

In humans

Although phages do not infect humans, there are countless phage particles in the human body, given our extensive microbiome. Our phage population has been called the human phageome, including the “healthy gut phageome” (HGP) and the “diseased human phageome” (DHP).JOURNAL, Manrique P, Bolduc B, Walk ST, van der Oost J, de Vos WM, Young MJ, Healthy human gut phageome, Proceedings of the National Academy of Sciences of the United States of America, 113, 37, 10400–10405, September 2016, 27573828, 5027468, 10.1073/pnas.1601060113, free, 2016PNAS..11310400M, The active phageome of a healthy human (i.e., actively replicating as opposed to nonreplicating, integrated prophage) has been estimated to comprise dozens to thousands of different viruses.JOURNAL, Minot S, Sinha R, Chen J, Li H, Keilbaugh SA, Wu GD, Lewis JD, Bushman FD, The human gut virome: inter-individual variation and dynamic response to diet, Genome Research, 21, 10, 1616–1625, October 2011, 21880779, 3202279, 10.1101/gr.122705.111, There is evidence that bacteriophages and bacteria interact in the human gut microbiome both antagonistically and beneficially.Preliminary studies have indicated that common bacteriophages are found in 62% of healthy individuals on average, while their prevalence was reduced by 42% and 54% on average in patients with ulcerative colitis (UC) and Crohn’s disease (CD). Abundance of phages may also decline in the elderly.The most common phages in the human intestine, found worldwide, are crAssphages. CrAssphages are transmitted from mother to child soon after birth, and there is some evidence suggesting that they may be transmitted locally. Each person develops their own unique crAssphage clusters. CrAss-like phages also may be present in primates besides humans.JOURNAL, Kirsch JM, Brzozowski RS, Faith D, Round JL, Secor PR, Duerkop BA, Bacteriophage-Bacteria Interactions in the Gut: From Invertebrates to Mammals, Annual Review of Virology, 8, 1, 95–113, September 2021, 34255542, 8484061, 10.1146/annurev-virology-091919-101238, free,

Commonly studied bacteriophages

Among the countless phages, only a few have been studied in detail, including some historically important phage that were discovered in the early days of microbial genetics. These, especially the T-phage, helped to discover important principles of gene structure and function.{{div col|colwidth=22em}}

• 186 phage
• λ phage
• Φ6 phage
• Φ29 phage
• ΦX174
• Bacteriophage φCb5
• G4 phage
• M13 phage
• MS2 phage (23–28 nm in size)JOURNAL, Strauss JH, Sinsheimer RL, Purification and properties of bacteriophage MS2 and of its ribonucleic acid, Journal of Molecular Biology, 7, 1, 43–54, July 1963, 13978804, 10.1016/S0022-2836(63)80017-0,
• N4 phage
• P1 phage
• P2 phage
• P4 phage
• R17 phage
• T2 phage
• T4 phage (169 kbp genome,JOURNAL, Miller ES, Kutter E, Mosig G, Arisaka F, Kunisawa T, Rüger W, Bacteriophage T4 genome, Microbiology and Molecular Biology Reviews, 67, 1, 86–156, table of contents, March 2003, 12626685, 150520, 10.1128/MMBR.67.1.86-156.2003, 200 nm longJOURNAL, Ackermann HW, Krisch HM, A catalogue of T4-type bacteriophages, Archives of Virology, 142, 12, 2329–2345, 6 April 2014, 9672598, 10.1007/s007050050246, 39369249, )
• T7 phage
• T12 phage

{{div col end}}

Bacteriophage databases and resources

• Phagesdb
• PhagescopeJOURNAL, Wang RH, Yang S, Liu Z, Zhang Y, Wang X, Xu Z, Wang J, Li SC, PhageScope: a well-annotated bacteriophage database with automatic analyses and visualizations, Nucleic Acids Research, 52, D1, D756–D761, January 2024, 37904614, 10767790, 10.1093/nar/gkad979, free,

See also

• Antibiotic
• Bacterivore
• CrAssphage
• CRISPR
• DNA viruses
• Macrophage
• Phage ecology
• Phage monographs (a comprehensive listing of phage and phage-associated monographs, 1921–present)
• Phagemid
• Polyphage
• RNA viruses
• Transduction
• Viriome
• Virophage, viruses that infect other viruses

References

{{Reflist|30em}}

Bibliography

• JOURNAL, Hauser AR, Mecsas J, Moir DT, Beyond Antibiotics: New Therapeutic Approaches for Bacterial Infections, Clinical Infectious Diseases, 63, 1, 89–95, July 2016, 27025826, 4901866, 10.1093/cid/ciw200,
• BOOK, Strathdee S, Patterson T, The Perfect Predator, 2019, Hachette Books, 978-0-316-41808-9,
• BOOK, Häusler T, Viruses vs. superbugs : a solution to the antibiotics crisis?, 2006, Macmillan, London, 978-1-4039-8764-8,

External links

{{Commons category}}

• WEB, The Bacteriophage Ecology Group,www.phage.org/, Abedon ST, The Ohio State University,www.phage.org/," title="web.archive.org/web/20130603163753www.phage.org/,">web.archive.org/web/20130603163753www.phage.org/, 3 June 2013,
• WEB, Tourterel C, Blouin Y, Orsay phage web site,bacteriophages.igmors.u-psud.fr/, Bacteriophages illustrations and genomics, 24 October 2013, 29 October 2013,bacteriophages.igmors.u-psud.fr/," title="web.archive.org/web/20131029192502bacteriophages.igmors.u-psud.fr/,">web.archive.org/web/20131029192502bacteriophages.igmors.u-psud.fr/, dead,
• WEB,www.ebi.ac.uk/pdbe/widgets/QuipStories/T4tail/T4tail.pdf, QuipStories: Bacteriophages get a foothold on their prey, PDBe,
• WEB, Flatow I,www.sciencefriday.com/program/archives/200804043, NPR, Science Friday podcast, Using ‘Phage’ Viruses to Help Fight Infection, April 2008,www.sciencefriday.com/program/archives/200804043," title="web.archive.org/web/20080417232145www.sciencefriday.com/program/archives/200804043,">web.archive.org/web/20080417232145www.sciencefriday.com/program/archives/200804043, 17 April 2008,
• WEB,www.youtube.com/watch?v=V73nEGXUeBY, Animation of a scientifically correct T4 bacteriophage targeting E. coli bacteria, YouTube,
• WEB,vimeo.com/8313889, Animation by Hybrid Animation Medical, T4 Bacteriophage targeting E. coli bacteria, 21 December 2009,
• {{YouTube|3VjE1zddXWk|Bacteriophages: What are they. Presentation by Professor Graham Hatfull, University of Pittsburgh}}

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