Fimbriae are important virulence factors for Salmonella pathogenesis. They mediate adhesion to host cells (including plants), food, stainless steel and much more. The fimbrial systems are organised in gene clusters of four to fifteen genes that code for structural, assembly and regulatory proteins. There are three kinds of fimbriae depending on their mode of assembly. The chaperone/usher (CU) fimbriae use a dedicated chaperone and usher protein to coordinate the subunit biogenesis on the cell surface. The curli fimbriae are assembled by nucleation/precipitation pathway. The type IV fimbria assembly requires a transmembrane apparatus and ATP to energise the reaction. Several fimbriae are conserved among Salmonella serovars, while some are present in a limited set or only specific serovars. Expression and regulation of fimbrial genes are not well understood, and most Salmonella fimbriae are poorly expressed during in vitro culture, which further complicates research concerning their regulation and role during infection. However, Salmonella fim gene cluster, coding for type-1 fimbriae, was widely studied and presents its own set of regulators. Investigating fimbrial distribution, expression and regulation will further elucidate their roles in bacterial pathogenesis and host specificity. Furthermore, fimbriae are important for developing efficient diagnostic tests and antimicrobial strategies against Salmonella.
- type IV fimbria
Multiple virulence factors are implicated in
Historically, the first observation of fimbriae was described in 1901 in
A specific fimbrial gene cluster (FGC) encodes for the structural, assembly and sometime regulatory proteins required for the production of the filamentous adhesive appendage on the bacterial surface. FGCs are usually composed of four to fifteen genes [10, 11]. An average of 12 FGCs by strains was observed in
In this chapter, an overview of
2. Fimbrial biogenesis pathways
Three pathways for fimbrial assembly exist in
The three pathways produce quite different fimbriae. CU fimbriae have the classic fimbrial shape with the repetition of major subunits emerging from the usher inserted in the outer membrane. The major subunits can be accompanied by minor subunits and/or adhesins . The fimbriae produced by the nucleation/precipitation pathway have an aggregated shape, due to the precipitation of major subunits together. This kind of fimbriae is highly stable and hardly depolymerised . The type IV fimbriae anchor in the inner membrane and are prolonged by the repetition of the major subunit (pilin) through the periplasm and the outer membrane reaching the extracellular medium . Here, the three fimbrial assembly mechanisms will be detailed.
2.1. Chaperone/usher pathway
The CU fimbriae represent the largest and most diversified class of adhesion systems [24, 25]. Multiple CU fimbriae are present in
The biogenesis of the CU fimbriae begins with the production of the subunits in the cytoplasm and their export through the inner membrane by the general secretory pathway (GSP) [23, 27, 28]. It consists in a post-translational translocation implying the SecYEG complex and SecDF/YajC proteins. When the pre-protein is produced, it can be targeted directly to the accessory factor SecA or transported to SecA by the general chaperone SecB. Then, SecA catalyses the hydrolysis of ATP to energise the translocation through SecYEG. Use of ATP, in combination with proton-motive force, triggers the transport of the pre-protein to the periplasm. During the translocation across the inner membrane, the N-terminal signal peptide is cleaved by periplasmic peptidases [27, 29]. To prevent early folding of the subunits, the fimbrial chaperone instantly forms a complex with the translocated subunit in the periplasm .
Fimbrial chaperone shares conserved structural features with the general periplasmic chaperones . They are formed of two β-sheet domains oriented to produce an L-shaped molecule and together form a β-barrel. Each domain has an immunoglobulin-like fold and is composed of seven primary β-strands [30–32]. Hydrophobic residues are alternated in the seven strands, facing the internal part of the barrel. These residues form the hydrophobic core of the domain that is implicated in the binding of the subunit. The fimbrial chaperones have an extended loop that lies at the extremity of one arm of the L-shaped molecule. This loop contains a conserved motif that is involved in the complex formation between the chaperone and subunits . The subunit and the chaperone have a similar structure, but the subunit is missing the seventh β-strand of the C-terminal extremity . The chaperone transfers the missing β-strand to the subunit to complete its structure: this mechanism is called the donor strand complementation . The chaperone preserves the folding energy of the subunit to drive the last steps of the assembly due to lack of energy source (ATP) in the periplasmic space . The chaperone also prevents premature fimbrial formation in the periplasm and primes the assembly through the usher [30, 34].
Then, the uncapping of the chaperone by the usher exposes the interactive surface of the subunit to the outer membrane usher and assembly of subunits at the surface can occur . The transfer of the subunit from the chaperone to the usher happens very rapidly in vivo. In the absence of the usher in vitro, only a slow and inefficient assembly was observed. This suggests that the uncapping of the chaperone is important for the efficiency of mature fimbriae assembly [28, 30]. An interaction between the usher and the subunit and also between the usher and the chaperone is required . This triangular interaction is important for the usher to discriminate subunit-loaded from unloaded chaperone . Fimbrial usher forms a ring in the outer membrane with a transient twin-pore of 2–3 nm diameter to allow passage of subunits to the extracellular environment . The usher catalyses fimbrial polymerisation by involving donor strand exchange where the N-terminal sequence of the subunit is replaced by a short sequence of the last subunit in the polymerised fibril with a zip-in-zip-out mechanism . This step is triggered in part by the chaperone required for the strand exchange between the new subunit and the forming fimbria. The quaternary structure of the subunit is achieved when the protein passes through the pore. The final morphology and structure (rigid or flexible), the length (1–3 μm) and width (2–10 nm) of the fibre of the CU fimbriae depend on the subunits composition and the interactions between subunits [10, 33].
2.2. Nucleation/precipitation pathway
Curli fimbriae were initially discovered in
The curli assembly mechanism is characterised by the exportation of the subunits and their precipitation to each other in the presence of a nucleator that fixes the fibril on the bacterial surface. Exportation of curli proteins also uses the GSP to pass through the inner membrane to the periplasm. Then, the CsgA and CsgB proteins are secreted by the lipoprotein CsgG. CsgG is composed of nine anticodon-binding domain-like units that form a 36-stranded β-barrel complex that is inserted in the outer membrane. CsgG forms a pore in the outer membrane that permits the passage of the subunits and the nucleator. CsgG is accompanied by the accessory proteins CsgE and CsgF. CsgE is a specificity factor that forms a nonameric adaptor that binds to CsgG and closes the periplasmic space. The presence of CsgE optimises the uptake of CsgA by CsgG and translocation of CsgA . CsgF helps the nucleation activity of CsgB. It was suggested that CsgF has a role in specific localisation and/or chaperoning of the nucleator, so CsgB will reach its full activity. Moreover, CsgF depends on CsgG and CsgE for its stability .
Once at the bacterial surface, the nucleator polymerises the subunits together into thin aggregative fimbriae (fibrils). This process happens only in the extracellular environment and requires the presence of the nucleator CsgB to polymerise CsgA into a filament. CsgA proteins fold into an insoluble cross β-sheet molecules . CsgB anchors the curli fimbriae on the surface of the bacterial cell (Figure 2). In
2.3. Type IV fimbriae
Type IV fimbriae are usually from 1 to 5 μm long and are composed of repeated subunits of a single pilin. Type IV fimbria is subdivided into two groups based on homology of the major subunits: type IVa and type IVb fimbriae . The difference between the two types is in the length of the peptide sequence and the mature major pilin sequence. Specific mechanism of assembly of type IVb fimbriae from
Type IV fimbriae pathway has the most complex machinery. They form an apparatus, composed of various proteins, that goes through the inner and outer membranes allowing the anchor of the fibre and energy accessibility for fimbrial assembly. The gene cluster also encodes numerous proteins with diverse functions, as the fibril is not only assembled but also disassembled. Type IV fimbriae are frequently compared to the type II secretion system (T2SS) which possesses similar structure and mechanism of assembly. Type IV fimbriae are implicated in adherence and twitching motility .
Type IV fimbriae are present in a variety of organisms including human pathogens such as
Each fimbrial pathway described above is present in
|Fimbriae||CU clade||Prevalence||Distribution||Fimbriae||CU clade||Prevalence||Distribution|
|γ1||Core||Absent in IV||γ4||Sporadic||IIIb |
|curli||Core||All ||π||Sporadic||IIIb, VI|
|γ1||Core||Absent in ||π||Sporadic||IIIb |
|γ1||Conserved||Absent in ID||γ3||Sporadic||IB, D (pseudo)|
|γ4||Sporadic||Only in Montevideo||β||Sporadic||VI |
|κ||Sporadic||Only in IA, IC and ||κ||Sporadic||IB, IE|
|γ4||Conserved||IB, IC, IIIa, VI, ||γ4||Sporadic||II |
|γ4||Sporadic||Only in Montevideo||γ4||Sporadic||ID|
|Sporadic||Type IV; ID, IE, ||γ4||Core||I, II, IIIb;|
|γ3||Conserved||ssp. I||γ4||Conserved||IA, IB, ID|
|γ4||Sporadic||π||Core||II, IIIa, missing in Gallinarum|
|π||Sporadic||π||Conserved||Missing in IA, IE|
|κ||Sporadic||IV, VI, ||π||Conserved||Missing in ID, IE|
|β||Sporadic||II ||γ1||Sporadic||ID, bongori|
|σ||Sporadic||IIIa ||γ1||Core||Missing IIIa and IIIb|
|γ1||Sporadic||IE, II, IIIa, IV||γ1||Conserved||Missing in ID|
|γ3||Sporadic||Tennessee (IE)||β||Sporadic||IA, IE|
|γ4||Sporadic||IIIb ||α||Sporadic||IC, ID, IE|
The distribution of the 38 FGCs gave a signature for each species, subspecies and serovars (Table 3). Seven FGCs, curli and the CU
Most cases of salmonellosis in humans are caused by
In addition to the seven core FGCs, five highly conserved FGCs (
Despite the presence of many FGCs, extensive gene degradation was observed in most of the host-restricted and warm-blooded host-adapted serovars, mainly Gallinarum, Choleraesuis, Paratyphi A and Typhi. Genome degradation of FGCs may correspond to the loss of genes rendered unnecessary by niche specialisation or by selective pressure in order to diminish antigen presentation at the bacterial surface during systemic disease. Intriguingly, most of FGCs were intact in Paratyphi B.
There are 11 FGCs that are not in ssp. I, with only
4. Fimbrial regulation
4.1. General regulation of fimbrial genes
Genes implicated in different aspects of virulence including motility, adhesion, invasion of host cells and intestinal persistence are all regulated during infection. It was proposed that there is a temporal hierarchy between the T3SS of SPI-1 (invasion), flagellar and fimbrial genes, where SPI-1 is first activated, followed by flagellar genes and then type-1 fimbrial genes (
Crosstalk regulation also occurs between the capsule and the type IVb fimbriae in
One of the post-transcriptional regulation mechanisms uses the binding of small RNAs and the Hfq chaperone. In an
Phase variation is a transcriptional mechanism that controls the switch between fimbriated (ON) and afimbriated (OFF) cells within a bacterial population. In
The secondary messenger cyclic-di-GMP controls virulence and biofilm formation in
In spite of all those known elements of regulation, how
4.2. Regulation of
fimin S. Typhimurium
At the opposite, FimW repressed directly
FimZ is also used as a regulator relay by two-component system for expression of
5. Fimbriae as a tool
Salmonelladetection using fimbrial genes
5.2. Vaccines development
As surface structures, fimbriae constitute antigens of choice for the development of vaccines against
More than 20 fimbrial antigens were detected in typhoid fever patient’s blood by transcriptomic analysis: SteD, StaACD, BcfDE, SafBC, TcfBCD, StbBC, FimAIDH, StdBC, StgACD and SthA . Antibodies against immunogenic fimbrial proteins TcfB, StbD and CsgEFG were identified in the blood of typhoid fever patients . Immunoreactive antibodies against SthDA and BcfA were found in lymphocytes supernatant (ALS) of patients with typhoid fever .
SefA, a protein from the SEF14 fimbriae of
As factors implicated in the first stages of infection, fimbriae are an interesting target for vaccine development . Fimbrial antigens are important for the development of new anti-
Fimbriae are diverse proteinaceous surface structures. They diverge by their assembly mechanisms and result in different filamentous structures with roles in pathogenesis. However, their roles are not completely understood. They were first known for adherence to cells and inert surfaces, but they seem to be implicated in so much more functions during infection.
The multiplicity of adhesion systems is also an enigma. Most of the
Regulation of fimbrial genes is a complex network that is tightly related to invasion and motility. Virulence factors are finely regulated, and a temporal expression hierarchy allows the success of
The actual understanding of fimbrial expression opens a new area on human health prevention. Some conserved fimbrial genes, in combination with other virulence genes, are precious markers for
A better understanding of fimbrial expression, production and regulation processes becomes important for prevention of
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