Abstract
In order for a successful infection and creating a satisfactory environment inside the host, strains of uropathogenic Escherichia coli (UPEC) need some special features that are achieved by expressing particular genes, called virulence factors. Two of the most important surface virulence factors of UPEC are type 1 fimbriae and P fimbriae that are crucial for the colonization process inside the urinary tract. Expression of these virulence factors converts a commensal strain into an uropathogen. Beside these factors, outer membrane proteins also contribute to virulence being involved in the secretory machinery; an example of such type is TolC protein that transfers α-hemolysin across the outer membrane of E. coli. However, α-hemolysin along with many other toxins serves various pathogenic roles during UTIs including adhesion, colonization, cytotoxic activity, etc. Moreover, virulence factors located on bacterial surface including capsule and lipopolysaccharides may also have the contribution to UTIs providing antiphagocytosis and antibactericidal complement activity.
Keywords
- virulent factors
- E. coli
- UPEC
- urinary tract infection
- type 1 fimbriae
- P fimbriae
- α-hemolysin
- cytotoxic necrotizing factor 1 (CNF1)
- siderophores
- hemin uptake system
- flagellar motility
1. Introduction
The most commonly living microorganism of the human gastrointestinal tract and also the most common causative agent of bacterial urinary tract infection is
In Gram-negative and some Gram-positive bacteria, virulence genes are allocated in particular segments (about 10–200 kilo bases in size) of their genome which have different G + C content than the other parts of the genome that are termed as pathogenicity islands. They are present in the virulent strains but present rarely in the nonpathogenic strains of the same species. These sequences can be transferred horizontally from species to species [12]. Pathogenicity islands encode virulence factors such as adherence factors, toxins, and iron acquisition systems which are important virulence factors of UPEC.
2. Adhesion
Urine of uninfected person is sterile due to urinary flow and antimicrobial activity of uric acid. Regular flow of urine does not allow microorganism to colonize inside the urinary tract. However, attachment of
In gram-negative bacteria like UPEC, adhesins are unveiled by chaperone-usher-assisted pathway. This pathway involves two proteins, one is a periplasmic chaperone, and the other is a protein called usher. Usher act as the base of the structure, and the function of chaperone is folding and recruitment of the subunits [17, 18]. In absence of the chaperone, pilin proteins are degraded and misfolded and thus cannot be assembled in the form of a mature pilus. On the other hand, usher helps to mature the fimbriae and its transportation through the outer assuring integrity of the outer membrane. The constituents of usher proteins are an N-terminal domain (NTD), 24-stranded beta-barrel channel, a plug domain, and two C-terminal domains (CTD). In uropathogenic
2.1. Type 1 fimbriae
In 99% of
2.2. P fimbriae
P-fimbriated
There are at least nine genes in the pap gene cluster with two restriction sites at two ends. The regulatory part starts the following Eco R1 consisting of papI and papB. Then papA, papH, papC, papD, papE, papF, and papG are situated, and after these, Bam HI is present. Approximately 1000 of subunits form a P fimbria, being united in a helical manner. Among them the major constituent is the protein subunit PapA (19.5 KD), and minor subunits are PapE (16.5 KD), PapF (15 KD), and PapG (35 KD). In the periplasmic space, PapD (27.5 KD) may be present and can also be incorporated in the structure. Another protein PapC, which is the largest one with 80 KD of mass, assists the process by transporting the subunits outside the part of the cell. Though PapA is the major constituent, it is not mandatory for attachment, and among many serotypes, PapA molecules show high homology with the amino acids of N and C termini. PapA also has an average level of similarity with structural subunits of other
Many experiments show that expression of these fimbriae is not relevant to urinary tract infection, while more sophisticated other experiments have concluded about their role in pathogenesis. However, during infection in immunocompromised patients, less expression of P fimbriae is observed, which indicated that P fimbriae are needed to overcome certain types of host immune attacks. Although P fimbriae can initiate inflammatory responses by activating TLR4 [24], it protects UPEC from human polymorphonuclear leukocytes (hPMNLs). In the rapidly changing environment through the urinary tract, environmental influences affect the expression of P fimbriae. Expression of P fimbriae is favored at 37°C and inhibited at a range of 18–22 °C, but there are some variations in this phenomenon. The temperature-dependent expression is controlled by a region close to
2.3. Dr/Afa adhesins
Dr blood group antigen is a membrane protein of red blood cells and located on the decay accelerating factor (DAF) that protects red blood cells from being degraded or lysed by autologous complements. Another important function of DAF is to regulate complement cascade [25]. These antigens are recognized by Dr and Afa adhesin family of uropathogenic
2.4. Other fimbriae as virulence factors
F1C is a virulence factor responsible for urinary tract infections, which is encoded by an operon of seven genes, i.e.,
3. Toxins
Several toxic substances or proteins secreted by uropathogenic strains of
3.1. α-hemolysin
Among all the toxins, α-hemolysin (HlyA) is very important which is a lipoprotein and belongs to the RTX (repeats in toxin) toxins family [13, 29, 30]. HlyA is a pore-forming toxin and causes inducible nitric-oxide-synthase (iNOS)-mediated cell membrane injury and apoptosis [31]. However, HlyA can lyse erythrocytes and nucleated host cells at high concentration by a process enabling UPEC which may damage the host immune effector cells for gaining enhanced access to the host nutrients and iron stores. But when the concentration is low, HlyA can induce the apoptosis of target host cells and promote the exfoliation of bladder epithelial cells [13, 32, 33]. Besides, HlyA can also contribute to nephropathogenicity, which was proved by infecting mice transurethrally or intravesically with toxin producer and nonproducer isogenic clone pairs of
3.2. Cytotoxic necrotizing factor 1 (CNF1)
Another virulence factor secreted by
3.3. Secreted autotransporter toxin (SAT)
Secreted autotransporter toxin (SAT) may also be important as a virulence factor for the pathogenesis of UTIs being had a toxin activity against cell lines of bladder or kidney origin. SAT is a serine protease autotransporter which falls within one subgroup of autotransporters recently classified as the SPATE (serine protease autotransporters of
3.4. Cytolethal distending toxin (CDT)
Cytolethal distending toxin, having a unique property of damaging the DNA of the target cell, was first reported in pathogenic
3.5. Other toxins
Some others including cytolysin A and toll/interleukin (IL-1) receptor (TIR) domain-containing protein (Tcp) are also considered as virulence factors in UTIs [46, 47]. The former causes apoptosis of the host cells [47], while the other has the ability to subvert TLR signaling that gives a survival advantage during UTIs [46]. However, Tcp is associated with pyelonephritis but rare in environmental
In addition to these toxins, vacuolating autotransporter toxin (VAT), Shigella enterotoxin-1 (ShET-1) and arginine succinyltransferase (AST) may also contribute to UTIs. VAT has the cytotoxic effect on the bladder and kidney, while the two others are involved in the invasion of the infections [48]. However, VAT is a highly protected immunogenic protein that belongs to the protease family of SPATE [28].
4. Siderophores
Iron is a very important molecule for all living beings, and
4.1. Aerobactin
Aerobactin is a low-weight molecule and a hydroxamate siderophore with a higher Fe3+-binding stability in acidic environments and is maximally produced at low pH [44, 53]. This siderophore extracts Fe3+ from host iron-binding proteins and is taken up through an outer membrane receptor protein [44]. However, aerobactin has many advantages over other siderophores and is formed from the condensation of two lysine molecules and one citrate catalyzed by an enzyme named aerobactin synthase [13, 25, 30].
4.2. Enterobactin
Enterobactin is another specialized highly prevalent catecholate siderophore which is less soluble and less stable than aerobactin [53, 54, 55]. But this siderophore has a higher iron affinity and can deferrate transferrin more rapidly than aerobactin in aqueous solution [13, 54]. However, iron is released from enterobactin through the hydrolysis of this siderophore [13]. Besides these, enterobactin may afford UPEC the ability to colonize within an iron-limiting environment such as the urinary tract [56]. But this siderophore has a limitation that it can be inactivated by host proteins such as serum albumin and siderocalin [25].
4.3. Yersiniabactin
Yersiniabactin, a mixed-type siderophore, is widespread in
4.4. Salmochelin
Salmochelin is a glucosylated derivative of enterobactin which is not recognized by siderocalin and thus escapes from the host immune response [53]. However, siderocalin, neutrophil gelatinase-associated lipocalin is also known as lipocalin 2 that binds enterobactin and prevents its uptake [53, 56]. To overcome this, enterobactin is modified to salmochelin by glucosylation via the action of glucosyltransferase and is not recognized by lipocalin 2 [56]. However, a recent study found that salmochelin siderophore receptor IroN is involved in the invasion of urothelial cells, and thus IroN may play both an iron uptake receptor and an internalization factor in the establishment of urinary tract infections [26].
4.5. Hemin uptake system
There is another iron acquisition system called hemin uptake system including ChuA and Hma, which involves direct upregulation of haem receptors. This system uptakes free iron during UTIs, and several studies found its role in bacterial growth and biofilm formation [48, 58, 59]. ChuA expression is regulated by other regulatory proteins, for instance, in uropathogenic
5. Capsule
The main role of a capsule is to cover and protect the bacterium from various unfavorable conditions as well as the host immune system, which is mainly constituted of polysaccharide [1]. The capsule provides protection against engulfment and complement-mediated bactericidal effect in the host, also including antimicrobial resistance and antiserum activity [1, 48]. Certain capsulars, such as K1 and K5, prevent a proper humoral immune response of the infected host by showing a molecular mimicry to tissue components [1]. The K1 polysaccharide, a linear α2–8-linked sialic acid homopolymer, has a very important role in IBC development as well as in the multiple stages of UTI pathogenesis [27, 50].
6. Lipopolysaccharide
Lipopolysaccharide (LPS) is an integral component of the cell wall and consists of the highly conserved lipid A-core and repeating O-antigen subunits that differ greatly between strains based on the sugar residues and their linkage patterns within the repeating subunits [37, 61]. LPS is very well known to activate host response and to induce nitric oxide and cytokine (IL-1, TNF-α) production which enhances the inflammatory response [1, 15]. It also induces the synthesis of specific antibodies to the somatic antigen and exerts an immune-adjuvant effect that promotes the humoral immune response to other antigens of the pathogen. However, certain antigenic types of LPS are also involved in resistance of the pathogen to the killing effect of the normal human serum [46]. According to study upon animal models, acute renal failure due to LPS depends on the systemic response to LPS and does not depend on expression of functional LPS receptor, TLR4, in the kidney. But it is not clear whether LPS plays a role in mediating a renal failure and acute allograft injury in patients with ascending UTIs [1].
7. Motility
Flagellum is an organelle that is responsible for bacterial motility and plays a role in the initial adhesion phase of biofilm formation [1, 62]. A recent study showed that motility is involved in the migration of the infection from the bladder to the kidneys [63]. About 70–90% of all urinary tract infections is caused by flagellated UPEC, and pathogenesis involves contact between the bacteria and epithelial cell surface of the urinary tract [1]. However, flagellar motility enhances the ability of
8. Mechanism of immune escape
Toll-like receptor 4 (TLR4) in the epithelial cells of the mammalian bladder can recognize lipopolysaccharides (LPS) of bacterial cell wall, and the downstream signaling cascade produces IL-6 and IL-8, of which IL-8 is well known as an important chemoattractant for neutrophils. Urinary levels of IL-6 and IL-8 are measurable in UPEC-infected human and murine models. There is another pathway parallel to this one that is responsible for increased levels of IL-6 and IL-8 in urine. Upon TLR-4 activation by LPS, intracellular level of cAMP is increased and results in of Ca2+ influx. Later, cAMP response element-binding protein (CREB) becomes phosphorylated. Phosphorylation of CREB results in the expression of IL-6 and IL-8 [24]. Mutation in TLR4 in murine models revealed its role on bacterial pathogenesis. There are other receptors related to UTI pathogenesis. One of such is CXCR1, but there are both types of evidences that demonstrate the positive and “no correlation” of CXCR1 with recurrent UTIs. Polymorphisms in IL-8 genes were found to have a correlation with pyelonephritis in the case of no correlation with CXCR1 mutation [19, 64]. TLR4 can be activated by the presence of type 1 fimbriae and P fimbriae.
As there are enough studies to evidence the activation of immune response against UPEC strains, there must be some ways that are used by these bacteria to overcome unfavorable situations early in the infection. Incubation of human urothelial cells with type 1-fimbriated UPEC strains resulted in increased apoptosis. In the case of a nonpathogenic type 1-fimbriated strain (HB101) of
Another indispensable way is the expression of toll/IL-1 receptor domain-containing protein (TcpC), which was discovered in UPEC strain CFT073. TcpC interacts with myeloid differentiation primary response 88 (MyD88), a protein that, in human, is encoded by
Modification of capsular lipopolysaccharides specific to the pathogenic strain can cause the failure of TLR4 to recognize the pathogen. However, LPS biosynthetic genes encoded by
9. Conclusions
Several epidemiological, serological, and bacteriological studies revealed that uropathogenic
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