**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.

**References**

Nephrology. 2012:e681473

biology. 2004;**2**(2):123

*coli*. Pathogens. 2016;**5**(1):2

Childhood. 1984;**59**(2):180

biology Reviews. 1991;**4**(1):80-128

1997;**23**(6):1089-1097

2016;**6**:18109

of *Escherichia coli*. PLoS One. 2013;**8**(1):e52835

national Journal of Infectious Diseases. 2009;**13**(2):140-144

Annals of Internal Medicine. 1989;**111**(11):906-917

sor CRP-cAMP. PLoS Pathogens. 2009;**5**(2):e1000303

Médico del Hospital Infantil de México. 2018;**75**(2):67-78

[1] Bien J, Sokolova O, Bozko P. Role of uropathogenic *Escherichia coli* virulence factors in development of urinary tract infection and kidney damage. International Journal of

Virulence Factors of Uropathogenic *E. coli* http://dx.doi.org/10.5772/intechopen.79557 17

[2] Wurpel DJ, Beatson SA, Totsika M, Petty NK, Schembri MA. Chaperone-usher fimbriae

[3] Farajnia S, Alikhani MY, Ghotaslou R, Naghili B, Nakhlband A. Causative agents and antimicrobial susceptibilities of urinary tract infections in the northwest of Iran. Inter-

[4] Johnson JR, Stamm WE. Urinary tract infections in women: Diagnosis and treatment.

[5] Simmering JE, Tang F, Cavanaugh JE, Polgreen LA, Polgreen PM. The increase in hospitalizations for urinary tract infections and the associated costs in the United States, 1998-2011. Open Forum Infectious Diseases. Oxford University Press. 2017;**4**(1):e281 [6] Müller CM, Åberg A, Straseviçiene J, Emődy L, Uhlin BE, Balsalobre C. Type 1 fimbriae, a colonization factor of uropathogenic *Escherichia coli*, are controlled by the metabolic sen-

[7] Kaper JB, Nataro JP, Mobley HL. Pathogenic *Escherichia coli*. Nature Reviews Micro-

[8] Luna-Pineda VM, Ochoa S, Cruz-Córdova A, Cázares-Domínguez V, Vélez-González F, Hernández-Castro R, et al. Urinary tract infections, immunity, and vaccination. Boletín

[9] Vizcarra IA, Hosseini V, Kollmannsberger P, Meier S, Weber SS, Arnoldini M, et al. How type 1 fimbriae help *Escherichia coli* to evade extracellular antibiotics. Scientific Reports.

[10] Olson PD, Hunstad DA. Subversion of host innate immunity by uropathogenic *Escherichia* 

[11] Winberg J. P-fimbriae, bacterial adhesion, and pyelonephritis. Archives of Disease in

[12] Hacker J, Blum-Oehler G, Mühldorfer I, Tschäpe H. Pathogenicity islands of virulent bacteria: Structure, function and impact on microbial evolution. Molecular Microbiology.

[13] Johnson JR. Virulence factors in *Escherichia coli* urinary tract infection. Clinical Micro-

[14] Riegman N, Die I, Leunissen J, Hoekstra W, Bergmans H. Biogenesis of F71 and F72 fimbriae of uropathogenic *Escherichia coli*: Influence of the FsoF and FstFG proteins and

localization of the Fso/FstE protein. Molecular Microbiology. 1988;**2**(1):73-80

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 *E. coli*, rate of apoptosis was approximately 50% of that of pathogenic strains of UPEC [65]. UPEC blocks NF-ĸB, and this results in apoptosis and a decreased cytokine secretion.

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 *MYD88* gene. Interaction of TcpC and MyD88 subsequently stops downstream signaling pathways mediated by TLRs.

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 *rfa, rfb* operons, and *surA* are the factors responsible for the suppression of TLR-initiated signaling cascades. Biosynthesis of a number of outer membrane proteins and fimbriae is facilitated by the protein encoded by surA, which is a periplasmic cis-trans prolyl isomerase [66, 67].
