**3.5. Other toxins**

**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 *E. coli* [34]. A recent study showed that HlyA regulates the dephosphorylation of Akt, which is a multifunctional signaling regulator and responsible for controlling inflammatory responses in the host, as well as the cell cycle control [35]. Moreover, HlyA has the role in the increased

12 Microbiology of Urinary Tract Infections - Microbial Agents and Predisposing Factors

production of IL-6 and IL-8 by inducing Ca2+ oscillations in renal epithelial cells [36].

Another virulence factor secreted by *E. coli* named cytotoxic necrotizing factor 1 (CNF1) is also involved in UTIs and stimulates actin stress fiber formation and membrane ruffle formation in a Rho GTPase-dependent manner that results in the entry of *E. coli* into the cells [37]. The toxin has a remarkable effect on the actin skeletal of HEp-2 cells and produces large vacuoles in HEp-2 cells [28]. However, several in vitro and in vivo studies showed that this protein interferes with polymorphonuclear phagocytosis and evokes apoptotic death of bladder epithelial cells and may lead to bladder cell exfoliation and to enhanced bacterial access to underlying tissue [38, 39]. In addition, there is also a possibility of the association of CNF1 with the hemolysin in the virulence mechanism, which is beneficial for the bacteria [28].

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 *Enterobacteriaceae*) family and associated with pyelonephritic *E. coli* strains [40, 41]. SAT may have the cytopathic activity that results in the damage of the host tissue and may increase the propagation ability of the UPEC. However, this toxin may facilitate entry of pyelonephritogenic strains into the bloodstream resulting from specific damage to the glomeruli and proximal tubules [40].

Cytolethal distending toxin, having a unique property of damaging the DNA of the target cell, was first reported in pathogenic *E. coli* in 1987 [28, 42]. This toxin has the ability to arrest the cell cycle and contributes to the pathogenesis of UTIs [43, 44]. However, CDT is an operon product encoding three proteins including CdtA, CdtB, and CdtC proteins which are encoded

**3.2. Cytotoxic necrotizing factor 1 (CNF1)**

**3.3. Secreted autotransporter toxin (SAT)**

**3.4. Cytolethal distending toxin (CDT)**

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 *E. coli*, in fecal flora of healthy children and in less severe forms of UTI [27]. Besides these, Tcp has also the role in the human avoidance system and cytopathic effect on the kidney [48].

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].
