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Pilus

A pilus (Latin for "hair"; plural, pili) is a filamentous proteinaceous appendage projecting from the surface of many prokaryotic cells, particularly bacteria, that facilitates adhesion to host tissues, environmental surfaces, or other microbes, and enables processes such as motility, biofilm formation, and horizontal gene transfer.^[1] These structures are typically 1–10 μm in length and 3–10 nm in diameter, composed of repeating subunits of pilin proteins that polymerize into a helical filament.^[2] Pili are classified into several types based on their assembly mechanisms, length, and primary functions, with major categories including chaperone-usher (CU) pili, sortase-assembled (SA) pili, and type IV pili, predominantly in Gram-negative bacteria but also present in some Gram-positive species.^[1] CU pili, such as type 1 and P pili in Escherichia coli, are assembled in the periplasm via chaperone proteins that stabilize pilin subunits through donor-strand complementation, followed by polymerization at an outer membrane usher complex, resulting in rigid, rod-like fibers tipped with adhesins that bind specific host receptors like mannose or Galα1–4Gal carbohydrates.^[1] In contrast, SA pili in Gram-positive bacteria like Streptococcus pyogenes rely on sortase enzymes to form covalent isopeptide bonds between pilin subunits bearing LPXTG motifs, anchoring the pilus to the cell wall peptidoglycan and enabling focal assembly at cell division sites.^[1] Type IV pili, subdivided into IVa (e.g., in Pseudomonas aeruginosa) and IVb (e.g., toxin-coregulated pili in Vibrio cholerae), exhibit dynamic assembly and disassembly, allowing extension and retraction powered by ATPases, which generate forces exceeding 100 pN to drive twitching motility across surfaces.^[3] These pili consist of pilin subunits with a conserved N-methylated α-helical core and a C-terminal disulfide bond, forming flexible, hollow filaments that not only mediate adhesion and microcolony formation but also facilitate DNA uptake for natural transformation and phage attachment.^[3] Functionally, pili are critical for bacterial pathogenesis, as they promote colonization of host mucosal surfaces—such as the urinary tract by uropathogenic E. coli via FimH adhesin-mediated attachment—and evasion of immune clearance, including resistance to phagocytosis in streptococci.^[2]^[1] Conjugative pili, a subset like the F-pilus in E. coli, form a pilus bridge between donor and recipient cells, enabling the transfer of plasmids carrying antibiotic resistance or virulence genes through a hollow core.^[2] Beyond infection, pili contribute to biofilm development, interbacterial aggregation, and environmental adaptation, making them targets for anti-virulence therapies that disrupt assembly or adhesion without killing bacteria.^[1]^[3]

Introduction

Definition

A pilus (plural: pili) is a thin, hair-like, proteinaceous appendage that projects from the surface of many bacterial and archaeal cells.^[4]^[5] These structures are primarily composed of pilin proteins, which polymerize to form filamentous shafts.^[6]^[2] The singular form "pilus" contrasts with the plural "pili," and these appendages are also commonly referred to as fimbriae, though the latter term often specifically denotes shorter, non-conjugative adhesive types, while "pili" may encompass longer variants such as the sex pilus.^[7]^[8]^[2] Synonyms like "sex pilus" highlight specialized forms involved in genetic exchange.^[2]^[9] Pili occur in both Gram-negative and Gram-positive bacteria, as well as in archaea, with genomic analyses revealing their presence in species across nearly all bacterial and archaeal phyla.^[5]^[10]^[11] As surface projections, they serve as key mediators of intercellular interactions among prokaryotes.^[12]^[2]

Distinction from Other Appendages

Pili differ from flagella, another prominent bacterial surface appendage, in several key structural and functional aspects. While flagella typically measure about 20 nm in diameter and enable swimming motility through a rotary motor powered by the proton motive force, pili are thinner, ranging from 3 to 10 nm in diameter, and do not support swimming; instead, certain types, such as type IV pili, facilitate surface-associated twitching motility via cycles of extension and retraction without a rotary mechanism.^[13]^[14]^[5] Furthermore, flagella are primarily composed of flagellin proteins arranged in a helical filament, whereas pili consist of pilin subunits that polymerize into a more rigid, straight filament.^[5]^[12] The terminology surrounding pili has historically overlapped with that of fimbriae, leading to early confusion in the literature. In the 1950s, researchers like Houwink and van Iterson described these non-flagellar appendages simply as "filaments," but Duguid et al. introduced the term "fimbriae" in 1955 to denote fringe-like structures involved in adhesion, a name that gained widespread adoption.^[15] Brinton later proposed "pili" in 1959, emphasizing their hair-like appearance and roles in conjugation, which helped resolve ambiguities by distinguishing conjugative pili (now often called sex pili) from adhesive fimbriae based on function and antigenicity.^[15] Today, "pilus" and "fimbria" are sometimes used interchangeably for non-motile appendages, but "pili" specifically highlights assemblies like type IV or conjugative types, avoiding conflation with broader terms.^[16] Unlike generic bacterial nanofibers, such as curli or amyloid fibers, or two-dimensional surface layers (S-layers), pili represent specialized, filamentous appendages dedicated to targeted functions like conjugation or type-specific adhesion. Nanofibers like curli form extracellular matrices for biofilm stability but lack the dynamic assembly-disassembly cycles characteristic of pili, while S-layers provide a protective crystalline coat rather than protruding filaments.^[10] This specificity underscores pili as distinct from these other prokaryotic nanostructures, which do not mediate DNA transfer or pilus-dependent motility.^[17] A notable physical distinction is the fragility of pili compared to the more robust flagella. Pili are easily sheared from the cell surface during mechanical agitation, such as vortexing or blending, due to their thin, flexible structure, allowing isolation for study without compromising cell viability; this contrasts with flagella, which, while also shearable, maintain greater rigidity from their helical design and basal body anchoring.^[18]^[5] This property facilitates experimental analysis of pilus assembly but highlights their vulnerability in natural environments subject to fluid shear forces.^[19]

Structure

Morphology and Dimensions

Pili are filamentous, hair-like appendages that protrude from the bacterial cell envelope as slender rods, exhibiting either rigid or flexible characteristics depending on the type, and frequently assembling into bundles on the cell surface.^[20] These structures enable various interactions with the environment, with their overall morphology providing a foundation for functional roles.^[21] In terms of dimensions, pili generally range from 3 to 10 nm in diameter and 0.3 to 20 μm in length, with variations influenced by the bacterial species and pilus subtype.^[20] For instance, the F-pilus of Escherichia coli measures approximately 8.5 nm in diameter and can extend up to 20 μm, featuring a central lumen of about 3 nm.^[21] Many pili display a helical architecture, with some incorporating supercoiling that enhances flexibility and adaptability during extension or retraction.^[22] The protein subunits composing these filaments contribute to this helical organization, allowing for structural polymorphism within the same pilus.^[21] Bacteria can produce up to several hundred pili per cell, with distribution patterns that are either polar, concentrated at the cell poles, or peritrichous, spread across the entire surface.^[20] Electron microscopy techniques, such as cryo-electron microscopy and negative staining, are essential for visualizing these nanoscale structures, often revealing variations in pilus length that correlate with antigenic diversity in bacterial populations.^[21]

Composition and Antigenic Properties

The primary structural component of bacterial and archaeal pili is the pilin protein, which forms the major repeating subunit of the pilus filament, typically with a molecular weight of 10 to 30 kDa. These pilins are synthesized as precursors and processed by prepilin peptidases to remove leader peptides, resulting in mature subunits that can be either glycosylated or non-glycosylated depending on the organism and pilus type; for instance, O-linked glycosylation occurs on serine or threonine residues in many type IV pilins, enhancing stability and function. Minor pilin subunits, distinct from the major pilin, are incorporated at the pilus tip or base and often mediate specific adhesion to host surfaces or other cells.^[23]^[24] Pilin subunits assemble through helical polymerization into a long, flexible tube-like fiber, with typically around 3.5-4 pilins per helical turn forming a hollow core about 2-3 nm in diameter. A key feature contributing to this architecture's stability is the post-translational N-methylation of the phenylalanine residue at the mature N-terminus (N-methylphenylalanine), which promotes proper subunit interactions and filament integrity during extrusion. Additional post-translational modifications include intramolecular disulfide bonds between conserved cysteine residues in the pilin's variable domain, which rigidify the structure in bacterial type IV pili, and lipid modifications such as prenylation in some archaeal surface structures to facilitate membrane anchoring and environmental resilience.^[25]^[23]^[26] Antigenic properties of pili arise from variability in pilin sequences, enabling phase and antigenic variation that promotes immune evasion by pathogens. This variation often occurs through genetic mechanisms like site-specific recombination or gene conversion, where segments of silent pilin genes are integrated into the expressed locus; in Neisseria gonorrhoeae, for example, RecA-dependent recombination between the expressed pilE gene and multiple silent pilS loci generates diverse pilin alleles, with strains exhibiting up to 20 distinct sequences to alter surface epitopes and avoid antibody recognition. Pili also display overall stability characteristics, being acid-labile under low pH conditions that disrupt hydrogen bonds in the helical structure, and capable of disassembly in sodium dodecyl sulfate (SDS) at room temperature without boiling, allowing subunit separation for analysis.^[27]

Biogenesis

Assembly Processes

Pilus biogenesis varies by type and Gram status, with major pathways including chaperone-usher (CU) in Gram-negatives, sortase-assembled (SA) in Gram-positives, and type IV in both. Assembly generally begins with the synthesis of pilin precursors in the cytoplasm, which are then translocated across the inner membrane via the Sec secretion pathway and processed by leader peptidases to remove their N-terminal leader sequences.^[28] These mature pilins are subsequently exported to the appropriate membrane (outer membrane in Gram-negatives or cytoplasmic membrane in Gram-positives) through dedicated secretion systems, where polymerization occurs to form the pilus fiber.^[28] This process differs by machinery, such as the chaperone-usher pathway in systems like Type 1 pili.^[29] In type IV and similar systems, the polymerization step is powered by ATP hydrolysis, driven by cytoplasmic assembly ATPases such as PilB-like motors, which provide the energy to force pilin subunits through the membrane channel and add them to the growing fiber tip. In contrast, CU pili assembly relies on chaperone-mediated donor-strand exchange at the usher for thermodynamic polymerization without ATP, while SA pili polymerization is catalyzed by sortase enzymes forming covalent bonds.^[28] In dynamic type IV pili involved in motility, the fiber can extend and retract through cycles of polymerization and depolymerization; retraction is energized by ATP hydrolysis from dedicated ATPases like PilT, which disassemble the pilus from the base.^[30] These ATPases ensure rapid turnover, allowing bacteria to respond to environmental cues.^[31] At the membrane, assembly platforms facilitate pilin extrusion; for instance, secretin porins like PilQ form multimeric gates in type IV systems, while CU ushers (e.g., FimD) and SA sortases provide analogous functions while maintaining membrane integrity.^[28] The overall biogenesis timeline is efficient, progressing from cytoplasmic precursors to a mature, functional pilus fiber in seconds to minutes, depending on the system and environmental conditions.^[32] This rapid assembly enables timely deployment of pili for adhesion or other functions.^[31]

Genetic Regulation

The genetic regulation of pilus production in bacteria primarily involves polycistronic operons that encode multiple components essential for assembly, including pilin subunits, chaperones, ushers, and accessory regulators. For instance, in Gram-negative bacteria, the fim operon in Escherichia coli consists of genes such as fimA (encoding the major pilin), fimC and fimD (chaperone and usher), and regulatory elements that coordinate expression as a single transcriptional unit.^[33] Similarly, in Gram-positive bacteria, pilus gene clusters like the spa operon in Corynebacterium diphtheriae organize pilins (spaA, spaB) with sortase enzymes for polymerization, ensuring stoichiometric production of assembly machinery.^[34] These operon structures allow for efficient, coordinated transcription under promoter control, often integrated into pathogenicity islands or plasmids to facilitate horizontal transfer.^[33] Phase variation, a key regulatory mechanism, enables reversible on-off switching of pilus expression in response to environmental cues such as temperature, pH, and quorum sensing signals. In the fim operon, this is mediated by site-specific recombination of an invertible DNA element (fimS), a 314-base-pair segment that repositions the promoter to activate or silence fimA transcription; inversion is catalyzed by recombinases like FimB and FimE, with rates influenced by growth conditions like neutral pH favoring expression.^[35] Temperature shifts, such as from 26°C to 37°C, upregulate pilus genes in pathogens like Yersinia pestis via thermosensitive regulators, while low pH enhances expression in Streptococcus pyogenes to promote adhesion during infection.^[33] Quorum sensing integrates population density signals to fine-tune operon activity, preventing premature pilus deployment.^[34] Global regulators, including nucleoid-associated proteins and sigma factors, overlay operon-specific control to integrate pilus expression with cellular stress responses. The histone-like nucleoid-structuring protein H-NS represses pilus genes under non-permissive conditions, while leucine-responsive regulatory protein (Lrp) and cAMP receptor protein (CRP) modulate phase variation by binding promoter regions in response to nutrient availability.^[33] The RpoS sigma factor, central to the general stress response, promotes pilus gene transcription during stationary phase or oxidative stress, coordinating with secretion systems for adaptive virulence.^[36] This layered regulation reflects evolutionary conservation, where core operon architectures and recombinase-based switching are preserved across Gram-negative and Gram-positive bacteria, often co-regulated with type II/III secretion pathways to synchronize surface structure deployment with environmental challenges.^[34]^[33] Mutations in regulatory elements profoundly impact pilus production and bacterial fitness. Loss-of-function mutations in recombinases like FimE lock the invertible element in the "off" orientation, abolishing phase variation and reducing adhesion in uropathogenic E. coli.^[33] Similarly, disruptions in global regulators such as H-NS or RpoS derepress or abolish pilus expression, leading to avirulent phenotypes; for example, rpoS mutants in Salmonella exhibit impaired stress tolerance and colonization defects due to uncoordinated pilus assembly.^[36] In Pseudomonas aeruginosa, mutations in pilus regulators like PilY1 diminish twitching motility and virulence in host models, underscoring how regulatory integrity is crucial for pathogenesis.

Functions

Conjugation

Conjugation is a key function of certain pili in bacteria, enabling the direct transfer of genetic material between donor and recipient cells through a process mediated by the type IV secretion system (T4SS). The pilus serves as a bridge that establishes physical contact between the cells, facilitating the formation of a conjugation pore through which single-stranded DNA (ssDNA) is transferred from the donor to the recipient. Recent live-cell imaging studies have confirmed that the F-pilus can also act as a conduit for ssDNA transfer between physically distant cells, without requiring full retraction.^[37] This transfer is initiated and guided by the relaxase enzyme, which covalently binds to the ssDNA and directs it across the pore.^[38] The process unfolds in distinct steps. First, the pilus extends from the donor cell surface to probe and attach to a nearby recipient cell, often retracting to bring the cells into close, wall-to-wall contact. Upon attachment, the relaxosome complex—comprising the relaxase and accessory proteins—recognizes the origin of transfer (oriT) site on the conjugative plasmid and nicks one DNA strand, generating the transferable ssDNA strand. This ssDNA is then pumped through the T4SS channel into the recipient, where the relaxase catalyzes its recircularization, followed by synthesis of the complementary strand using the recipient's replication machinery to establish the plasmid.^[38] Conjugation requires intimate cell-cell contact and exhibits variable efficiency, typically ranging from 10^{-4} to 10^{-2} transconjugants per donor cell under standard laboratory conditions, though this can increase in dynamic environments or biofilms. Fluid flow in environments can further enhance conjugation by generating hotspots that increase donor-recipient encounters and pilus-mediated contacts.^[39] This mechanism plays a pivotal role in horizontal gene transfer, allowing the dissemination of conjugative plasmids that often carry genes for virulence factors or antibiotic resistance, thereby accelerating bacterial adaptation and contributing to the global rise of multidrug-resistant pathogens.^[40]^[38] Recent studies have highlighted how pilus dynamics influence conjugation outcomes in clinical contexts. In 2023, research on the F-pilus demonstrated its biomechanical adaptability, including elasticity and stability under hydrodynamic stress, which enhances conjugation efficiency of resistance plasmids in environments mimicking clinical settings, such as those with fluid flow or agitation, thereby promoting biofilm formation and plasmid spread among pathogens like Escherichia coli.^[41]

Adhesion and Biofilm Formation

Bacterial pili play a crucial role in adhesion by facilitating the initial attachment of cells to host tissues and environmental surfaces through specialized tip adhesins that recognize and bind specific receptors. These adhesins, often located at the distal end of the pilus, enable precise interactions, such as mannose-specific binding observed in certain pili that target glycosylated host cell surfaces. For instance, in Escherichia coli, type 1 pili exemplify this mechanism with their FimH adhesin promoting attachment to mannose-containing receptors on epithelial cells.^[42] In biofilm formation, pili serve as anchors, securing bacterial cells to inert substrates and fostering community development by linking adjacent cells through intercellular pilus-pilus or pilus-adhesin interactions. This aggregation promotes the formation of microcolonies, the foundational units of biofilms, enhancing structural integrity and resistance to environmental stresses. Non-piliated mutants exhibit significant defects in biofilm biomass and stability, underscoring the essential anchoring and cohesive functions of pili.^[42]^[43] Pili also integrate with motility mechanisms, such as twitching or gliding, to facilitate biofilm maturation by enabling cells to explore surfaces, disperse aggregates, and establish multilayered communities. This dynamic process allows bacteria to optimize positioning within the biofilm matrix, contributing to its expansion and heterogeneity.^[42] Piliated bacteria demonstrate markedly enhanced adhesion compared to non-piliated counterparts, as measured in systems involving shear-dependent binding. This amplification is critical for withstanding hydrodynamic forces in host environments or flow conditions.^[44] Furthermore, pili enable adaptation to abiotic surfaces, such as those of medical devices, by promoting irreversible attachment to materials like polystyrene and polymers used in catheters or implants. Adhesins like CsuE in Acinetobacter baumannii exemplify this capability, driving colonization that leads to persistent biofilm-related infections.^[42]^[45]

Types

Conjugative Pili

Conjugative pili are extracellular filamentous appendages specialized for facilitating DNA transfer during bacterial conjugation, predominantly in Gram-negative bacteria that carry conjugative plasmids. These structures, a functional variant of type IVb pili, enable horizontal gene transfer, allowing the dissemination of genetic elements such as antibiotic resistance genes across bacterial populations. Unlike motility-focused type IVa pili, conjugative pili are primarily dedicated to establishing physical connections between donor and recipient cells. They are widely distributed in species including Escherichia coli, Pseudomonas spp., and other Enterobacteriaceae, where they are encoded by plasmid-borne operons.^[46] Structurally, conjugative pili are characterized by their robust, cylindrical form, with a diameter of approximately 8-9 nm and lengths extending up to 20 μm, though they can vary in rigidity and flexibility depending on the plasmid system. They are composed of repeating subunits of the TraA pilin protein, a processed 70-amino-acid peptide derived from a larger pro-pilin precursor, which assembles into a helical polymer often incorporating phospholipids for stability. A hallmark feature is their retractability, driven by dedicated ATPases, enabling the pilus to extend from the donor cell surface, contact a recipient, and then retract to draw cells into close proximity, forming a stable mating pair. This dynamic assembly ensures efficient plasmid mobilization without permanent attachment.^[46]^[47] Assembly of conjugative pili occurs through the Type IV secretion system (T4SS), a multiprotein complex homologous to the Agrobacterium tumefaciens VirB/VirD4 system. Key components include VirB4-like ATPases (e.g., TraB in the F system) for energy-dependent polymerization, the VirD4-type coupling protein (TraD) for substrate recruitment, and outer membrane secretins (TraF homologs) that anchor the pilus tip. The TraA pilin subunits are inserted into the inner membrane via leader peptidase B and the proton motive force, followed by chaperone-assisted polymerization at the inner membrane and extrusion through the T4SS channel. This process is tightly regulated by plasmid-encoded genes, ensuring pilus formation only under conducive environmental conditions.^[46]^[47]^[48] The primary function of conjugative pili is to stabilize the mating pair, creating a conduit for single-stranded plasmid DNA transfer from donor to recipient, though the pilus itself may not directly channel the DNA in all systems. This stabilization is critical for the efficiency of conjugation, as pilus retraction brings cells into direct membrane contact, allowing subsequent T4SS-mediated DNA translocation. Recent studies have demonstrated that the biomechanical properties of these pili, such as elasticity and force generation during retraction, enhance transfer rates, accelerating the spread of conjugative plasmids carrying antibiotic resistance determinants in clinical and environmental settings.^[46]^[41] Prominent examples include the F-pilus of Escherichia coli, encoded by the IncF incompatibility group plasmid, which exemplifies the classic retractable structure optimized for broad-host-range transfer in Enterobacteriaceae. Another key instance is the RP4 pilus associated with the IncP broad-host-range plasmid in Pseudomonas spp., featuring a rigid, thin morphology that supports conjugation across diverse Gram-negative genera, including soil and pathogenic bacteria.^[46]^[49]

Type IV Pili

Type IV pili (T4P) are thin, flexible filamentous structures, typically 5-8 nm in diameter and up to several micrometers in length, that extend from the surface of many Gram-negative bacteria and archaea.^[50] These pili are primarily composed of thousands of copies of a major pilin subunit, often denoted as PilA, which forms the helical fiber core through polymerization.^[51] At the distal tip, minor pilins such as PilE, PilV, PilW, and PilX assemble into a complex that facilitates initial surface interactions and modulates pilus dynamics.^[52] The assembly of T4P involves a dynamic cycle of extension and retraction powered by dedicated ATPases. Extension is driven by the cytoplasmic ATPase PilB, which provides energy for pilin polymerization and extrusion through the outer membrane via the secretin pore formed by PilQ.^[53] Retraction, essential for motility, is mediated by the depolymerizing ATPase PilT, which disassembles the pilus fiber from the base, generating pulling forces up to 100 pN.^[53] This outside-in assembly pathway ensures rapid cycles, with the inner membrane platform proteins PilC, PilM, PilN, PilO, and PilP anchoring the system.^[54] T4P mediate key functions including twitching motility, where coordinated extension and retraction propel cells across surfaces at speeds of 0.1-2 μm/s, and autoaggregation through tip-mediated cell-cell adhesion.^[55] In bacteria like Pseudomonas aeruginosa, T4P enable pathogenic twitching motility, facilitating colonization of host tissues and biofilm formation on medical devices.30250-2) Similarly, in Neisseria gonorrhoeae, these pili promote adhesion to epithelial cells, a critical step in infection.30250-2) T4P systems are highly conserved across bacteria and archaea, where archaeal type IV-like pili (T4aP) often serve adhesion roles in extreme environments.^[56] A 2024 structural study revealed two dramatically distinct T4P architectures in the archaeon Saccharolobus islandicus, both formed by pilins with identical sequences but differing in helical parameters and flexibility to adapt to diverse habitats.^[57]

Type 1 Pili

Type 1 pili, also known as type 1 fimbriae, are adhesive surface structures primarily produced by Gram-negative bacteria, enabling specific attachment to host cells during infection.^[58] These pili are assembled through the chaperone-usher (CU) pathway and are particularly prominent in uropathogenic Escherichia coli (UPEC), where they play a key role in urinary tract infections (UTIs).^[59] Unlike other pilus types, type 1 pili are rigid, non-motile appendages specialized for host adhesion rather than bacterial conjugation or movement.^[28] Structurally, type 1 pili form rigid, helical rods approximately 7 nm in diameter and 1-2 μm in length, composed mainly of thousands of repeating FimA pilin subunits arranged in a right-handed helix with about 3.3 subunits per turn.^[58] At the distal tip, a short fibrillum includes the adhesin FimH, along with FimG and FimF adapter subunits, which positions FimH for host receptor binding.^[59] This architecture provides mechanical stability, allowing the pilus to withstand shear forces during host colonization.^[60] The overall design was elucidated through seminal cryo-electron microscopy and X-ray crystallography studies, revealing the immunoglobulin-like folds of the pilin subunits.^[61] Assembly of type 1 pili occurs via the CU pathway in the periplasm and outer membrane of Gram-negative bacteria. Individual pilin subunits (FimA, FimF, FimG, FimH) are exported to the periplasm, where the chaperone FimC binds each subunit in a 1:1 complex, stabilizing their incomplete immunoglobulin-like domains through donor-strand complementation—wherein FimC's G1 β-strand temporarily completes the subunit's fold to prevent aggregation.^[58] The usher protein FimD, an outer membrane β-barrel, then recruits chaperone-subunit complexes sequentially, catalyzing pilus polymerization by facilitating donor-strand exchange: each incoming subunit displaces the chaperone's strand and donates its own to the growing pilus tail.^[59] This process anchors the mature pilus to the outer membrane, with up to 500 pili potentially assembled per cell in UPEC strains under optimal conditions.^[62] The CU pathway is exclusive to Gram-negative bacteria and absent in archaea, which employ distinct pilus assembly mechanisms.^[28] Functionally, type 1 pili mediate adhesion to mannosylated glycoproteins on host epithelial cells via the lectin activity of the FimH adhesin, which binds terminal α-D-mannose residues with high specificity.^[61] This attachment is crucial for UPEC colonization of the urinary tract, facilitating bacterial invasion of bladder epithelial cells and formation of intracellular bacterial communities (IBCs) that evade immune clearance.^[63] Expression of type 1 pili is phase-variable, controlled by invertible DNA elements in the fim operon that switch between ON and OFF states at rates of 10^{-3} to 10^{-4} per cell generation, allowing adaptation to different host niches.^[58] In UPEC, this enables persistent UTI pathogenesis, as phase variation optimizes adhesion during ascent from the bladder to the kidneys.^[60]

Sortase-Assembled Pili

Sortase-assembled (SA) pili are multimeric, covalently linked protein structures found on the surface of many Gram-positive bacteria, assembled through the action of sortase enzymes. These pili are crucial for adhesion, biofilm formation, and pathogenesis in various Gram-positive pathogens and commensals.^[64] Structurally, SA pili consist of pilin subunits linked by covalent isopeptide bonds formed between lysine residues of one subunit and threonine of the LPXTG motif in another. The pili form flexible filaments, often tipped with adhesin subunits that recognize specific host receptors. Major pilins form the shaft, while minor pilins serve as adhesins or stabilizers.^[64] Assembly occurs via class C sortases, which catalyze intermolecular transpeptidation between pilin subunits bearing LPXTG sorting motifs. The process is encoded by polycistronic operons containing pilin genes and sortase genes. A housekeeping sortase then anchors the assembled pilus to the cell wall peptidoglycan via lipid II intermediates. This mechanism allows for ordered polymerization, often at cell division sites, and is distinct from the chaperone-usher pathway in Gram-negatives.^[64]^[1] SA pili are prevalent in Gram-positive bacteria such as Streptococcus pyogenes (with FCT-1 pili mediating adhesion to host fibronectin), Streptococcus pneumoniae (pilus-1 contributing to nasopharyngeal colonization), Enterococcus faecalis (Ebp pili involved in endocarditis and biofilm formation), and Corynebacterium diphtheriae (SpaA-type pili for pharyngeal adherence). Functionally, they promote host tissue colonization, immune evasion, and interbacterial interactions, making them key virulence factors.^[64]

Curli

Curli are a class of amyloid-based pili primarily produced by bacteria in the Enterobacteriaceae family, such as Escherichia coli and Salmonella species, where they serve as key components of the extracellular matrix for surface adhesion.^[65] Unlike classical pili formed by covalent polymerization of pilin subunits, curli assemble through a non-covalent, self-templated process that results in protease-resistant fibers.^[66] These structures are particularly prominent under environmental stress conditions and contribute to bacterial persistence in host-associated biofilms.^[65] Structurally, curli consist of thin, non-helical amyloid fibers with a diameter of 4-7 nm and lengths extending up to several micrometers, forming tangled networks on the bacterial surface.^[67] The major structural subunit is CsgA, a 131-amino-acid protein rich in glutamine, asparagine, and glycine residues, which aggregates into β-sheet-rich fibrils stabilized by hydrogen bonding and hydrophobic interactions.^[68] A minor subunit, CsgB, integrates into the fiber as a nucleator, displaying conserved repeat regions (R1, R3, R5) that drive the amyloid fold, while the N- and C-terminal domains remain unstructured to facilitate polymerization.^[65] This cross-β architecture renders curli highly stable and resistant to denaturation, distinguishing them from the helical or rod-like forms of other pili.^[66] Assembly of curli occurs extracellularly via a nucleation-precipitation mechanism mediated by the type VIII secretion system.^[69] Unfolded CsgA monomers are secreted across the outer membrane through the CsgG channel, aided by chaperones CsgE and CsgF, and then associate with surface-anchored CsgB to initiate templated polymerization into fibers.^[65] This process requires no enzymatic catalysis beyond secretion, relying instead on the intrinsic amyloidogenic properties of CsgA and CsgB, and results in non-covalent aggregates that are irreversible under physiological conditions.^[66] Functionally, curli promote adhesion to abiotic surfaces and host extracellular matrix components, such as fibronectin and laminin, enhancing bacterial colonization and community formation.^[65] They are integral to biofilm matrix architecture, providing mechanical stability and facilitating cell aggregation in mixed-species communities.^[66] Expression is tightly regulated by temperature, with optimal production at 26-30°C, though pathogenic strains can induce curli at 37°C to support persistence during infection.^[65] In Escherichia coli strains like O157:H7, curli enable chronic intestinal colonization and urinary tract infections by mediating tissue invasion and immune evasion.^[70] Similarly, in Salmonella enterica, curli (also termed thin aggregative fimbriae) contribute to systemic infections, including sepsis, by binding host plasminogen and promoting biofilm formation on gallstones.^[65] These roles underscore curli's impact on long-term bacterial survival in host environments.^[66] A key uniqueness of curli lies in their amyloid composition, which confers exceptional protease resistance—surviving treatments that degrade most protein polymers—due to the dense β-sheet packing.^[68] Unlike pilins in conjugative or type IV pili, which are often glycosylated and immunogenic, curli subunits lack such modifications, resulting in low antigenicity and reduced host immune recognition.^[65] This non-covalent, self-assembling nature also contrasts with chaperone-usher pathways, allowing rapid, energy-efficient production without periplasmic folding intermediates.^[66]

Role in Virulence and Applications

Pathogenic Mechanisms

Pili play a critical role in facilitating bacterial invasion of host tissues by mediating specific adhesion and penetration, thereby promoting tissue tropism and colonization. In uropathogenic Escherichia coli (UPEC), type 1 pili enable attachment to mannosylated receptors on bladder epithelial cells via the tip adhesin FimH, triggering bacterial uptake and formation of intracellular communities that shield pathogens from urinary flow and immune clearance.^[71] Similarly, type IV pili in Pseudomonas aeruginosa promote adherence to and penetration of mucosal surfaces in the lungs, enhancing infectivity in cystic fibrosis and ventilator-associated pneumonia. The toxin-coregulated pilus (TCP), a type IV pilus variant in Vibrio cholerae, mediates tight adhesion to the intestinal epithelium, essential for cholera toxin delivery and diarrheal disease pathogenesis.^[72] Bacterial pili contribute to immune evasion through mechanisms such as antigenic variation and modulation of inflammatory responses. In Neisseria gonorrhoeae, phase and antigenic variation of type IV pilin proteins alters pilus structure, reducing opsonization by host antibodies and enabling persistent mucosal infections.^[73] Curli pili in enteric pathogens like Salmonella enterica and E. coli interact with Toll-like receptor 2 (TLR2) on host cells, provoking a pro-inflammatory cytokine response that can overwhelm innate defenses while aiding biofilm persistence.^[74] These interactions allow piliated strains to subvert phagocytosis and complement activation, prolonging survival in host environments. Quantitative studies underscore the impact of pili on virulence; for instance, type IV pilus mutants of P. aeruginosa exhibit approximately 10-fold reduced virulence in murine burn wound infection models compared to wild-type strains.^[75] In polymicrobial infections, such as chronic wounds or cystic fibrosis lungs, pili facilitate interspecies adhesion within biofilms, enhancing community stability and resistance to antimicrobials across bacterial consortia.^[76] This cooperative role amplifies overall pathogenicity in mixed infections.

Therapeutic Targeting

Therapeutic targeting of pili includes strategies to disrupt their roles in bacterial adhesion, conjugation, and biofilm formation, some of which aim to combat infections without directly killing bacteria to reduce the risk of resistance development. One prominent strategy involves inhibitors that block pilus-mediated adhesion. For Type 1 pili, mannose analogs target the adhesin FimH at the pilus tip, preventing binding to mannose-containing receptors on host cells and showing promise against urinary tract infections caused by uropathogenic Escherichia coli.^[77] These compounds, such as bivalent mannosides, exhibit high affinity and oral bioavailability, with preclinical studies demonstrating reduced bacterial colonization in mouse models of infection.^[78] For infections involving type IV pili, such as uncomplicated gonorrhea caused by Neisseria gonorrhoeae, zoliflodacin, an oral antibiotic that completed phase 3 trials in 2024 with a pending new drug application as of 2025, targets DNA gyrase to inhibit bacterial replication and has demonstrated microbiological cure rates over 90% even against multidrug-resistant strains.^[79]^[80] Vaccine development leverages pilin proteins as antigens to elicit immune responses against pilus assembly or function, particularly for pathogens like N. gonorrhoeae. Pilin-based vaccines, such as those using detoxified pilin subunits, have induced Th1-driven immunity and reduced bacterial adherence in animal models, but face challenges from antigenic variation in pilin sequences, which allows immune evasion and limits cross-protection.^[81]^[82] Ongoing efforts incorporate outer membrane vesicles with pilin epitopes to broaden immunogenicity, though clinical translation remains hindered by hypervariability and the need for mucosal immunity.^[83] Anti-biofilm agents target curli, the amyloid-like pili in enteric bacteria that stabilize biofilms on medical devices. Dispersin B, a glycoside hydrolase, hydrolyzes the polysaccharide matrix supporting curli structures, dispersing preformed biofilms and preventing reformation in Escherichia coli and Staphylococcus device-associated infections, with combinations showing synergistic effects alongside antibiotics.^[84]^[85] This approach reduces biofilm persistence on medical devices in vitro, offering a non-lethal alternative to combat chronic biofilm-related complications. Recent advances include CRISPR-based strategies to disrupt conjugative pili and limit antibiotic resistance gene transfer. In 2024, a Mobile-CRISPRi system delivered via conjugative plasmids targeted integron genes such as intI1 in Escherichia coli, reducing horizontal gene transfer by approximately 1000-fold.^[86] This precision approach curbs the spread of multidrug resistance plasmids, with potential for engineered phages to enhance delivery in clinical settings. Looking to the future, pilus disassembly enzymes represent a novel antibiotic class by specifically degrading assembled pili to impair adhesion and biofilm integrity. Recent studies as of 2025 have identified druggable targets within type IV pilus assembly machinery for antivirulence therapies against Pseudomonas aeruginosa and Neisseria species.^[87] Inhibitors of sortase enzymes, which anchor pilins during assembly, have shown efficacy in preclinical models against Gram-positive pili, suggesting disassembly-promoting hydrolases could evolve into targeted therapies that restore host clearance mechanisms while minimizing microbiome disruption.^[88] These enzyme-based interventions, potentially delivered via nanoparticles, hold promise for treating persistent infections like those on indwelling devices.^[89]

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