Escherichia coli is the main etiological agent of urinary tract infections. Its virulence factors are important during the initial interaction stage with the host as they enable colonization of urinary tract tissues. The genetic markers evidencing susceptibility to develop recurrent infections have been previously described. Toll-like receptors are critical sensors of microbial attacks, and they are also effectors of the individual’s innate defense for elimination of pathogens. The aim of this study was to evaluate the association between functional polymorphisms (896 A>G, 1196 C>T, − 2570 A>G, − 2081 G>A) and susceptibility to develop urinary tract infections as well as E. coli virulence factors. This study includes 100 samples from patients diagnosed with UTI and 100 samples from uninfected subjects. A conventional urine culture was performed and the isolates were identified by using the Vitek automated system. TLR4 gene polymorphisms were identified by the PCR–RFLP technique. The hlyA, fimH, papC, iutA and cnf1 virulence factors as well as the E. coli phylogenetic group were assessed by PCR. In this study, it was observed that the presence of the − 2570 polymorphism represents a risk of UTI (p < 0.01), whereas − 2081 confers protection (p < 0.01). The 896A>G and 1196C>T polymorphisms were associated with the E. coli virulence factors fimH and hlyA, respectively (p < 0.05). The B2 group was the most frequent in clinical isolates (51%), and it displayed more virulence factors regarding other phylogenetic groups (p ≤ 0.05). An interesting finding was that strains considered as commensals, belonging to groups A and B1, can cause UTI and present virulence factors. Polymorphisms occurring in the TLR4 promoter region are correlated with susceptibility or risk of UTI, whereas structural polymorphisms are associated with the recognition of virulence factors displayed by E. coli.
TLR-4 Polymorphisms Uropathogenic Escherichia coliPhylogenetic group Virulence factors
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This work was supported by the Fondo FOMIX-CONACYT Gobierno del Estado de Guerrero Convocatoria M0008 2014-01 (No. 249671).
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest related to this study.
This article does not contain any studies with human participants performed by any of the authors.
Informed consent was obtained from all individual participants included in the study.
Scholes D, Hooton TM, Roberts PL, Stapleton AE, Gupta K, Stamm WE. Risk factors for recurrent urinary tract infection in young women. J Infect Dis. 2000;182(4):1177–82.CrossRefGoogle Scholar
Scholes D, Hooton TM, Roberts PL, Gupta K, Stapleton AE, Stamm WE. Risk factors associated with acute pyelonephritis in healthy women. Ann Intern Med. 2005;142(1):20–7.CrossRefGoogle Scholar
Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med. 2002;113(Suppl 1A):5S–13S.CrossRefGoogle Scholar
Spencer JD, Schwaderer AL, Becknell B, Watson J, Hains DS. The innate immune response during urinary tract infection and pyelonephritis. Pediatr Nephrol. 2014;29(7):1139–49.CrossRefGoogle Scholar
Abraham SN, Miao Y. The nature of immune responses to urinary tract infections. Nat Rev Immunol. 2015;15(10):655–63.CrossRefGoogle Scholar
Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25(2):187–91.CrossRefGoogle Scholar
Bryant CE, Gay NJ, Heymans S, Sacre S, Schaefer L, Midwood KS. Advances in toll-like receptor biology: modes of activation by diverse stimuli. Crit Rev Biochem Mol Biol. 2015;50(5):359–79.CrossRefGoogle Scholar
Behzadi P, Behzadi E, Ranjbar R. IL-12 family cytokines: general characteristics, pathogenic microorganisms, receptors, and signalling pathways. Acta Microbiol Immunol Hung. 2016;63(1):1–25.CrossRefGoogle Scholar
Song J, Abraham SN. TLR-mediated immune responses in the urinary tract. Curr Opin Microbiol. 2008;11(1):66–73.CrossRefGoogle Scholar
Jin MS, Lee JO. Structures of the toll-like receptor family and its ligand complexes. Immunity. 2008;29(2):182–91.CrossRefGoogle Scholar
Frendeus B, Wachtler C, Hedlund M, Fischer H, Samuelsson P, Svensson M, et al. Escherichia coli P fimbriae utilize the toll-like receptor 4 pathway for cell activation. Mol Microbiol. 2001;40(1):37–51.CrossRefGoogle Scholar
Fischer H, Yamamoto M, Akira S, Beutler B, Svanborg C. Mechanism of pathogen-specific TLR4 activation in the mucosa: fimbriae, recognition receptors and adaptor protein selection. Eur J Immunol. 2006;36(2):267–77.CrossRefGoogle Scholar
Chakraborty DC, Mukherjee G, Banerjee P, Banerjee KK, Biswas T. Hemolysin induces toll-like receptor (TLR)-independent apoptosis and multiple TLR-associated parallel activation of macrophages. J Biol Chem. 2011;286(40):34542–51.CrossRefGoogle Scholar
Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol. 2001;1(2):135–45.CrossRefGoogle Scholar
Hagberg L, Hull R, Hull S, McGhee JR, Michalek SM, Svanborg Eden C. Difference in susceptibility to gram-negative urinary tract infection between C3H/HeJ and C3H/HeN mice. Infect Immun. 1984;46(3):839–44.PubMedPubMedCentralGoogle Scholar
Ferwerda B, McCall MB, Verheijen K, Kullberg BJ, van der Ven AJ, Van der Meer JW, et al. Functional consequences of toll-like receptor 4 polymorphisms. Mol Med. 2008;14(5–6):346–52.PubMedPubMedCentralGoogle Scholar
Rubi-Castellanos R, Martinez-Cortes G, Munoz-Valle JF, Gonzalez-Martin A, Cerda-Flores RM, Anaya-Palafox M, et al. Pre-Hispanic Mesoamerican demography approximates the present-day ancestry of Mestizos throughout the territory of Mexico. Am J Phys Anthropol. 2009;139(3):284–94.CrossRefGoogle Scholar
de Cueto M. Microbiological diagnosis of urinary tract infections. Enferm Infecc Microbiol Clin. 2005;23(Suppl 4):9–14.CrossRefGoogle Scholar
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16(3):1215.CrossRefGoogle Scholar
Ragnarsdottir B, Jonsson K, Urbano A, Gronberg-Hernandez J, Lutay N, Tammi M, et al. Toll-like receptor 4 promoter polymorphisms: common TLR4 variants may protect against severe urinary tract infection. PLoS ONE. 2010;5(5):e10734.CrossRefGoogle Scholar
Lorenz E, Frees KL, Schwartz DA. Determination of the TLR4 genotype using allele-specific PCR. Biotechniques. 2001;31(1):22–4.CrossRefGoogle Scholar
De Staercke C, Lally C, Austin H, Winston C, Dowling N, Williams B, et al. The lack of association between four point mutations in the promoter region of the toll-like 4 receptor gene and myocardial infarction. Thromb Res. 2007;119(1):105–10.CrossRefGoogle Scholar
Scott VC, Haake DA, Churchill BM, Justice SS, Kim JH. Intracellular bacterial communities: a potential etiology for chronic lower urinary tract symptoms. Urology. 2015;86(3):425–31.CrossRefGoogle Scholar
Godaly G, Ambite I, Svanborg C. Innate immunity and genetic determinants of urinary tract infection susceptibility. Curr Opin Infect Dis. 2015;28(1):88–96.PubMedGoogle Scholar
Mody L, Juthani-Mehta M. Urinary tract infections in older women: a clinical review. JAMA. 2014;311(8):844–54.CrossRefGoogle Scholar
Minardi D, d’Anzeo G, Cantoro D, Conti A, Muzzonigro G. Urinary tract infections in women: etiology and treatment options. Int J Gen Med. 2011;4:333–43.CrossRefGoogle Scholar
Hawn TR, Scholes D, Li SS, Wang H, Yang Y, Roberts PL, et al. Toll-like receptor polymorphisms and susceptibility to urinary tract infections in adult women. PLoS ONE. 2009;4(6):e5990.CrossRefGoogle Scholar
Wiles TJ, Mulvey MA. The RTX pore-forming toxin alpha-hemolysin of uropathogenic Escherichia coli: progress and perspectives. Future Microbiol. 2013;8(1):73–84.CrossRefGoogle Scholar
Pitout JD. Extraintestinal pathogenic Escherichia coli: a combination of virulence with antibiotic resistance. Front Microbiol. 2012;3:9.CrossRefGoogle Scholar
Clermont O, Christenson JK, Denamur E, Gordon DM. The Clermont Escherichia coli phylo-typing method revisited: improvement of specificity and detection of new phylo-groups. Environ Microbiol Rep. 2013;5(1):58–65.CrossRefGoogle Scholar
Millan Y, Hernandez E, Millan B, Araque M. Distribution of phylogenetic groups and virulence factors in CTX-M-15 beta-lactamase-producing uropathogenic Escherichia coli strains isolated from patients in the community of Merida, Venezuela. Rev Argent Microbiol. 2014;46(3):175–81.PubMedGoogle Scholar
Miranda-Estrada LI, Ruiz-Rosas M, Molina-Lopez J, Parra-Rojas I, Gonzalez-Villalobos E, Castro-Alarcon N. Relationship between virulence factors, resistance to antibiotics and phylogenetic groups of uropathogenic Escherichia coli in two locations in Mexico. Enferm Infecc Microbiol Clin. 2014;35:426–33.CrossRefGoogle Scholar
Munkhdelger Y, Gunregjav N, Dorjpurev A, Juniichiro N, Sarantuya J. Detection of virulence genes, phylogenetic group and antibiotic resistance of uropathogenic Escherichia coli in Mongolia. J Infect Dev Ctries. 2017;11(1):51–7.CrossRefGoogle Scholar
Luthje P, Brauner A. Virulence factors of uropathogenic E. coli and their interaction with the host. Adv Microb Physiol. 2014;65:337–72.CrossRefGoogle Scholar
Behzadi E, Behzadi P. The role of toll-like receptors (TLRs) in urinary tract infections (UTIs). Cent Eur J Urol. 2016;69(4):404–10.Google Scholar