A bacteriophage (/bækˈtɪərioʊfeɪdʒ/), also known informally as a phage (/ˈfeɪdʒ/), is a virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek φαγεῖν (phagein), 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.^[2] 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.^[3] 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,^[4] where up to 9x10⁸ virions per millilitre have been found in microbial mats at the surface,^[5] and up to 70% of marine bacteria may be infected by bacteriophages.^[6]

Bacteriophages were used from the 1920s as an alternative to antibiotics in the former Soviet Union and Central Europe, as well as in France.^[7][8] They are seen as a possible therapy against multi-drug-resistant strains of many bacteria (see phage therapy).^{[9][10][11][12]}

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.^[13] Phage–host interactions are becoming increasingly important areas of research.^[14]

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.

ICTV classification of prokaryotic (bacterial and archaeal) viruses^[2]

Order	Family	Morphology	Nucleic acid	Examples
Belfryvirales	Turriviridae	Enveloped, isometric	Linear dsDNA
Caudovirales	Ackermannviridae	Nonenveloped, contractile tail	Linear dsDNA
	Autographiviridae	Nonenveloped, noncontractile tail (short)	Linear dsDNA
	Chaseviridae		Linear dsDNA
	Demerecviridae		Linear dsDNA
	Drexlerviridae		Linear dsDNA
	Guenliviridae		Linear dsDNA
	Herelleviridae	Nonenveloped, contractile tail	Linear dsDNA
	Myoviridae	Nonenveloped, contractile tail	Linear dsDNA	T4, Mu, P1, P2
	Siphoviridae	Nonenveloped, noncontractile tail (long)	Linear dsDNA	λ, T5, HK97, N15
	Podoviridae	Nonenveloped, noncontractile tail (short)	Linear dsDNA	T7, T3, Φ29, P22
	Rountreeviridae		Linear dsDNA
	Salasmaviridae		Linear dsDNA
	Schitoviridae		Linear dsDNA
	Zobellviridae		Linear dsDNA
Halopanivirales	Sphaerolipoviridae	Enveloped, isometric	Linear dsDNA
	Simuloviridae	Enveloped, isometric	Linear dsDNA
	Matshushitaviridae	Enveloped, isometric	Linear dsDNA
Haloruvirales	Pleolipoviridae	Enveloped, pleomorphic	Circular ssDNA, circular dsDNA, or linear dsDNA
Kalamavirales	Tectiviridae	Nonenveloped, isometric	Linear dsDNA
Ligamenvirales	Lipothrixviridae	Enveloped, rod-shaped	Linear dsDNA	Acidianus filamentous virus 1
	Rudiviridae	Nonenveloped, rod-shaped	Linear dsDNA	Sulfolobus islandicus rod-shaped virus 1
Mindivirales	Cystoviridae	Enveloped, spherical	Linear dsRNA	Φ6
Norzivirales	Atkinsviridae	Nonenveloped, isometric	Linear ssRNA
	Duinviridae	Nonenveloped, isometric	Linear ssRNA
	Fiersviridae	Nonenveloped, isometric	Linear ssRNA	MS2, Qβ
	Solspiviridae	Nonenveloped, isometric	Linear ssRNA
Petitvirales	Microviridae	Nonenveloped, isometric	Circular ssDNA	ΦX174
Primavirales	Tristromaviridae	Enveloped, rod-shaped	Linear dsDNA
Timlovirales	Blumeviridae	Nonenveloped, isometric	Linear ssRNA
	Steitzviridae	Nonenveloped, isometric	Linear ssRNA
Tubulavirales	Inoviridae	Nonenveloped, filamentous	Circular ssDNA	M13
	Paulinoviridae	Nonenveloped, filamentous	Circular ssDNA
	Plectroviridae	Nonenveloped, filamentous	Circular ssDNA
Vinavirales	Corticoviridae	Nonenveloped, isometric	Circular dsDNA	PM2
Durnavirales	Picobirnaviridae (proposal)	Nonenveloped, isometric	Linear dsRNA
Unassigned	Ampullaviridae	Enveloped, bottle-shaped	Linear dsDNA
	Autolykiviridae	Nonenveloped, isometric	Linear dsDNA
	Bicaudaviridae	Nonenveloped, lemon-shaped	Circular dsDNA
	Clavaviridae	Nonenveloped, rod-shaped	Circular dsDNA
	Finnlakeviridae	Nonenveloped, isometric	Circular ssDNA	FLiP[15]
	Fuselloviridae	Nonenveloped, lemon-shaped	Circular dsDNA	Alphafusellovirus
	Globuloviridae	Enveloped, isometric	Linear dsDNA
	Guttaviridae	Nonenveloped, ovoid	Circular dsDNA
	Halspiviridae	Nonenveloped, lemon-shaped	Linear dsDNA
	Plasmaviridae	Enveloped, pleomorphic	Circular dsDNA
	Portogloboviridae	Enveloped, isometric	Circular dsDNA
	Thaspiviridae	Nonenveloped, lemon-shaped	Linear dsDNA
	Spiraviridae	Nonenveloped, rod-shaped	Circular ssDNA

It has been suggested that members of Picobirnaviridae infect bacteria, but not mammals.^[16]

There are also many unassigned genera of the class Leviviricetes: Chimpavirus, Hohglivirus, Mahrahvirus, Meihzavirus, Nicedsevirus, Sculuvirus, Skrubnovirus, Tetipavirus and Winunavirus containing linear ssRNA genomes^[17] and the unassigned genus Lilyvirus of the order Caudovirales containing a linear dsDNA genome.

History

In 1896, Ernest Hanbury Hankin reported that something in the waters of the Ganges and Yamuna rivers in India had a marked antibacterial action against cholera and it could pass through a very fine porcelain filter.^[18] 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 bacteria^[19]

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."^[20] D'Hérelle called the virus a bacteriophage, a bacteria-eater (from the Greek phagein, meaning "to devour"). He also recorded a dramatic account of a man suffering from dysentery who was restored to good health by the bacteriophages.^[21] It was d'Hérelle who conducted much research into bacteriophages and introduced the concept of phage therapy.^[22] 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.^[23]

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.^[24] 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

Phages were discovered to be antibacterial agents and were used in the former Soviet Republic of Georgia (pioneered there by Giorgi Eliava with help from the co-discoverer of bacteriophages, Félix d'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."^[25]

They had widespread use, including treatment of soldiers in the Red Army.^[26] 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.^[27]
• Publication of research in the Soviet Union was mainly in the Russian or Georgian languages and for many years was not followed internationally.
• The Soviet technology was widely discouraged and in some cases illegal due to the infamous red scare.

The use of phages has continued since the end of the Cold War in Russia,^[28] 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.^[29] 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.^[29] 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.^[30] 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.^[30] 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.^[31]

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.^[5][6][7] 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.^[32]

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.^[33]

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.^[34]

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 104 °F (40 °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. ^[34]

Other

Food industry

Phages have increasingly been used to safen food products and to forestall spoilage bacteria.^[35] 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.^[36] In July 2007, the same bacteriophage were approved for use on all food products.^[37] In 2011 USDA confirmed that LISTEX is a clean label processing aid and is included in USDA.^[38] 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.^[39]

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. ^[40]

Diagnostics

In 2011, the FDA cleared the first bacteriophage-based product for in vitro diagnostic use.^[41] 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.^[42]

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.^[43] 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^[30] 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.^[44]

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.^[45]

Antimicrobial drug discovery

Phage proteins often have antimicrobial activity and may serve as leads for peptidomimetics, i.e. drugs that mimic peptides.^[46] 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.^[47]

Basic research

Bacteriophages are important model organisms for studying principles of evolution and ecology.^[48]

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.^[49] 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.^[50][35]

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.^[51]

Replication

The life cycle of bacteriophages tends to be either a lytic cycle or a lysogenic cycle. In addition, some phages display pseudolysogenic behaviors.^[13]

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.^[13] 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.^[52]

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.^[53]

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.^[54][55] Strategies to combat certain bacterial infections by targeting these toxin-encoding prophages have been proposed.^[56]

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