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Filamentous bacteriophage is a family of viruses (Inoviridae) that infect bacteria. The phages are named for their filamentous shape, a worm-like chain (long, thin and flexible, reminiscent of a length of cooked spaghetti), about 6 nm in diameter and about 1000-2000 nm long. The phage is assembled at the plasma membrane of the host bacteria from five types of protein, which are added to the nascent virion as it extrudes through the membrane. The simplicity of this family makes it an attractive model system to study fundamental aspects of molecular biology, and it has also proven useful as a tool in immunology and nanotechnology.

History
Three filamentous bacteriophages, fd, f1 and M13, were isolated and characterized by three different research groups in the early 1960s. The filamentous particle seen in electron micrographs was initially incorrectly interpreted as contaminating bacterial pilus, but ultrasonic degradation, which breaks flexible filaments roughly in half, inactivated infectivity as predicted for a filamentous bacteriophage morphology. Since these three phages differ by less than 2 percent in their DNA sequences, for many purposes they can be considered to be identical. Phages fd, f1, M13 and other related phages are often referred to as members of the Ff group of phages, for F specific (they infect Escherichia coli carrying the F-episome) filamentous phages. Further independent characterization over the subsequent half-century was shaped by the interests of these different research groups and their followers.The number of known filamentous bacteriophages has since multiplied many-fold by using a machine-learning approach, and it has been suggested that “the former Inoviridae family should be reclassified as an order, provisionally divided into 6 candidate families and 212 candidate subfamilies”.

Life cycle of Ff phages
Filamentous phages, unlike most other phages, are continually extruded through the bacterial membrane without killing the host. Genetic studies on M13 using conditional lethal mutants, initiated by David Pratt and colleagues, led to description of phage gene functions. Notably, the protein product of gene 5, which is required for synthesis of progeny single-stranded DNA, is made in large amounts in the infected bacteria, and it binds to the nascent DNA to form a linear intracellular complex. (The simple numbering of genes using Arabic numerals 1,2,3,4… introduced by the Pratt group is sometimes displaced by the practice, introduced by some f1 researchers, of using Roman numerals I, II, III, IV… but the gene numbers denoted by the two systems are the same).

Longer (or shorter) DNA can be included in fd phage, since more (or fewer) protein subunits can be added during assembly as required to protect the DNA, making the phage convenient for genetic studies. The length of the phage is also affected by the positive charge per length on the inside surface of the phage capsid. The genome of fd was one of the first complete genomes to be sequenced.

Structure and assembly
The molecular structure of Ff filamentous phage was determined using a number of physical techniques, especially X-ray fiber diffraction, and further refined using solid-state NMR and cryo-electron microscopy. The single-stranded Ff phage DNA runs down the central core of the phage, and is protected by a cylindrical protein coat built from thousands of identical α-helical major coat protein subunits. The two ends of the phage are capped by a few copies of minor proteins that are important for infection of the host bacteria, and also for assembly of nascent phage particles. The fiber diffraction studies identified two symmetry classes of phage, differing in the details of the arrangement of the major coat protein. Class I, including strains fd, f1, M13, If1 and IKe, has a rotation axis relating the major coat proteins, whereas Class II, including strains Pf1, Pf3, Pf4 and PH75, this rotation axis is replaced by a helix axis. This technical difference has little noticeable effect on the overall phage structure, but the extent of independent diffraction data is greater for symmetry Class II than for Class I. This assisted the determination of the Class II phage Pf1 structure, and by extension the Class I structure. The DNA isolated from fd phage is single-stranded, and topologically a circle. That is, the DNA single strand extends from one end of the phage particle to the other and then back again to close the circle, although the two strands are not base-paired. This topology was assumed to extend to all other filamentous phages, but it is not the case for phage Pf4, for which the DNA in the phage is single-stranded but topologically linear, not circular.

The p1 protein of Ff phage, which is required for phage assembly at the membrane, has a membrane-spanning hydrophobic domain with the N-terminal portion in the cytoplasm and the C-terminal portion in the periplasm (the reverse of the orientation of the gene 8 coat protein). Adjacent to the cytoplasmic side of the membrane-spanning domain is a 13- residue sequence of p1 having a pattern of basic residues closely matching the pattern of basic residues near the C terminus of p8, but inverted with respect to the sequence. Gene 1 is a conserved marker gene that (along with three additional genetic features) was used to automatically detect inovirus sequences.

Genetics
The gene 8 protein is inserted into the plasma membrane as an early step in phage assembly. Some strains of phage have a "leader sequence" on the gene 8 protein to promote membrane insertion, but others do not seem to need the leader sequence. These proteins are the products of phage genes 3 and 6 at one end of the phage, and phage genes 7 and 9 at the other end.

Biological and medical sciences
Filamentous bacteriophage engineered to display immunogenic peptides are useful in immunology. George Smith and Greg Winter used f1 and fd for their work on phage display for which they were awarded a share of the 2018 Nobel Prize in Chemistry. Filamentous bacteriophage can promote antibiotic tolerance by forming liquid crystalline domains around bacterial cells, and also by triggering maladaptive innate viral pattern-recognition responses, which impair bacterial clearance.

Materials sciences and nanotechnology
The creation and exploitation of many derivatives of M13 for a wide range of purposes, especially in materials science and nanotechnology, has been employed by Angela Belcher and colleagues.

Classification (taxonomy)
The taxonomy of filamentous bacteriophage was defined by Andre Lwoff and Paul Tournier as family Inophagoviridae, genus I. inophagovirus, species Inophagovirus bacterii (Inos=fiber or filament in Greek), with phage fd (Hoffmann-Berling) as the type species. "Phagovirus" is tautological, and the name of the family was altered to Inoviridae and the type genus to Inovirus. This nomenclature persisted for many decades, although the definition of fd as type species was replaced as M13 became more widely used for genetic manipulation.

Roux et al 2019

"suggested that the former Inoviridae family should be reclassified as an order, provisionally divided into 6 candidate families and 212 candidate subfamilies,"