The flagellin It is a protein of the filament, which is a structure that is part of the flagellum of bacteria. The vast majority of bacteria have only one type of flagellin. However, some have more than two.
The molecular size of this protein varies between 30 kDa and 60 kDa. For example, in Enterobacteriaceae its molecular size is large, while in certain freshwater bacteria it is small..
Flagellin is a virulence factor that allows host cell adhesion and invasion. In addition, it is a powerful activator of many types of cells involved in the innate and adaptive immune response..
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The flagellum is anchored to the cell surface. It consists of three parts: 1) the filament, which extends from the cell surface and is a rigid, hollow cylindrical structure; 2) the basal body, which is embedded in the cell wall and membrane layers, forming several rings; and 3) the hook, a short curved structure that joins the basal body to the filament.
The basal body is the most complex part of the flagellum. In gram negative bacteria it has four rings connected to a central column. In gram positive it has two rings. The rotational movement of the flagellum occurs in the basal body.
The location of flagella on the surface of bacteria varies widely between organisms, and can be: 1) monoteric, with only one flagella; 2) polar, with two or more; or 3) peritrichous, with many lateral flagella. There are also endoflagella, as in spirochetes, which are located in the periplasmic space.
Helicobacter pylori it is very mobile because it has six to eight unipolar flagella. A pH gradient through the mucus allows H. pylori is oriented and established in an area adjacent to the epithelial cells. Pseudomonas has a polar flagellum, which exhibits sugar chemotaxis and is associated with virulence.
A striking feature of the flagellin protein sequence is that its N-terminal and C-terminal regions are highly conserved, while the central region is highly variable between species and subspecies of the same genus. This hypervariability is responsible for hundreds of serotypes of Salmonella spp.
Flagellin molecules interact with each other through the terminal regions and polymerize to form a filament. In this, the terminal regions are located towards the inside of the cylindrical structure of the filament, while the central one is exposed towards the outside..
Unlike tubulin filaments that depolymerize in the absence of salts, those of bacteria are very stable in water. Approximately 20,000 subunits of tubulin form a filament.
In the filament of H. pylori Y Pseudomonas aeruginosa Two types of flagellin polymerize: FlaA and FlaB, encoded by the fliC gene. FlaAs are heterogeneous and are subdivided into several subgroups, with molecular masses that vary between 45 and 52 kDa. FlaB is homogeneous with a molecular mass of 53 kDa.
Frequently, the lysine residues of flagellins are methylated. In addition, there are other modifications such as glycosylation of FlaA and phosphorylation of tyrosine residues of FlaB, whose functions are, respectively, virulence and export signal..
The scourge of bacteria can be eliminated experimentally, making it possible to study its regeneration. The flagellin subunits are transported through the internal region of this structure. When they reach the extreme, the subunits are added spontaneously with the help of a protein (“cap protein”) called HAP2 or FliD.
The synthesis of the filament takes place by means of own assembly; that is, the polymerization of flagellin does not require enzymes or factors.
The information for the assembly of the filament is found in the subunit itself. Thus, the flagellin subunits polymerize to form eleven protofilaments, which form a complete one.
The flagellin synthesis of P. aeruginosa Y Proteus mirabilis is inhibited by antibiotics such as erythromycin, clarithromycin, and azithromycin.
The first studies showed that flagellin, at subnanomolar concentrations, from Salmonella, is a potent inducer of cytokines in a promonocytic cell line.
Subsequently, it was shown that the induction of the pro-inflammatory response involves an interaction between flagellin and the surface receptors of the cells of the innate immune system..
The surface receptors that interact with flagellin are the toll-5 type (TLR5). Subsequently, studies with recombinant flagellin showed that, when it lacked the hypervariable region, it was unable to induce an immune response..
TLR5s are present in cells of the immune system, such as lymphocytes, neutrophils, monocytes, macrophages, dendritic cells, epithelial cells, and lymph nodes. In the intestine, TLR5 regulates the composition of the microbiota.
Gram-negative bacteria typically use the type-III secretory system to translocate flagellin into the cytoplasm of the host cell, triggering a series of intracellular events. Thus, flagellin in the intracellular medium is recognized by proteins of the NAIP family (an apoptosis inhibitor protein / NLR family).
Subsequently, the flagellin-NAIP5 / 6 complex interacts with the NOD-like receptor, which generates the host's response to infection and damage..
Plants recognize this protein in a way sensing 2 of flagellin (FLS2). The latter is a leucine repeat-rich receptor kinase and is homologous to TLR5. FLS ”interacts with the N-terminal region of flagellin.
Binding of flagellin to FLS2 produces phosphorylation of the MAP kinase pathway, which culminates in the synthesis of proteins that mediate protection against infection by fungi and bacteria..
In some nightshade plants, flagellin can also bind to the FLS3 receptor. In this way, they protect themselves against pathogens that evade the defense mediated by FLS2..
An adjuvant is a material that increases the cellular or humoral response to an antigen. Because many vaccines produce a poor immune response, good adjuvants are necessary.
Numerous studies demonstrated the effectiveness of flagellin as an adjuvant. These investigations consisted of using recombinant flagellin in vaccines, evaluated using animal models. However, this protein has yet to pass Phase I of clinical trials..
Among the recombinant flagellins studied are: flagellin-epitope 1 of the influenza virus hematoglutinin; flagellin-epitope of Schistosoma mansoni; flagellin-heat stable toxin E. coli; flagellin -protein 1 from the surface of Plasmodium; and flagellin-envelope protein of the Nile virus, among other recombinants.
There are some advantages to using flagellin as an adjuvant in vaccines for human use. These advantages are as follows:
1) It is effective at very low doses.
2) They do not stimulate the IgE response.
3) The sequence of another adjuvant, Ag, can be inserted into the flagellin sequence without affecting the flagellin signaling pathway via TLR5.
Because flagellin genes exhibit wide variation, they can be used for specific detections, or for species or strain identification..
For example, the combination of PCR / RFLP has been used to study the distribution and polymorphism of flagellin genes in isolates of E. coli North America.
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