**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 [53–55]. 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].

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

Virulence Factors of Uropathogenic *E. coli* http://dx.doi.org/10.5772/intechopen.79557 15

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].

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 *E. coli* by adaptive responses to attractive or repellent environ-

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.

as in the multiple stages of UTI pathogenesis [27, 50].

**6. Lipopolysaccharide**

**7. Motility**

mental stimuli [15].

**8. Mechanism of immune escape**

### **4.3. Yersiniabactin**

Yersiniabactin, a mixed-type siderophore, is widespread in *Enterobacteriaceae* including *E. coli* and encoded on the high-pathogenicity island [53]. Yersiniabactin has a high iron affinity and produced yersiniabactin-Fe3+ complex binding to the iron molecule which recognizes the specific bacterial outer membrane TonB-dependent receptor and Fyu (Psn). The iron molecule is released from yersiniabactin in the cytosol with the help of membrane-embedded proteins [57]. In addition, this siderophore increases resistance to copper stress by chelating Cu2+ [10].

#### **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 *E. coli* strain 536, increase in RfaH level induces the expression of ChuA [60]. But the other receptor Hma functions independently of ChuA, and a residue, Tyr-126, is necessary for its function. However, both ChuA and Hma contribute to haem utilization which is required for the maximum kidney colonization [51].
