A Systematic Review of the (Un)known Host Immune Response Biomarkers for Predicting Recurrence of Urinary Tract Infection

Abstract

Recurrent urinary tract infections (rUTI) represent a major healthcare and economic burden along with a significant impact on patient's morbidity and quality of life, even in the absence of well-known risk factors, such as vesicoureteral reflux. Despite numerous attempts to find a suitable therapeutic option, there is no clear benefit of any currently available intervention for prevention of UTI recurrence and its long-term consequences such as hypertension, renal scarring and/or insufficiency. The common treatment practice in many centers around the globe involves the use of continuous low-dose antibiotic prophylaxis, irrespective of various studies indicating increased microbial resistance against the prophylactic drug, leading to prolonged duration and escalating the cost of UTI treatment. Moreover, the rapid appearance of multi-drug resistant uropathogens is threatening to transform UTI to untreatable disease, while impaired host-microbiota homeostasis induced by a long-term use of antibiotics predisposes patients for various autoimmune and infectious diseases. New biomarkers of the increased risk of UTI recurrence could therefore assist in avoiding such outcomes by revealing more specific patient population which could benefit from additional interventions. In this light, the recent findings suggesting a crucial role of urothelial innate immunity mechanisms in protection of urinary tract from invading uropathogens might offer new diagnostic, prognostic and even therapeutic opportunities. Uroepithelial cells detect uropathogens via pattern recognition receptors, resulting in activation of intracellular signaling cascade and transcription factors, which ultimately leads to an increased production and secretion of chemokines, cytokines and antimicrobial peptides into the urinary stream. Emerging evidence suggest that the disturbance of a single component of the urinary tract innate immunity system might increase susceptibility for rUTI. The aim of the current review is to update clinicians and researchers on potential biomarkers of host immune response alterations predisposing for rUTI and propose those well worth exploring further. For this purpose, over a hundred original papers were identified through an extensive PubMed and Scopus databases search. This comprehensive review might enrich the current clinical practice and fill the unmet clinical needs, but also encourage the development of therapeutic agents that would facilitate urinary bacterial clearance by enhancing the host immune response.

Keywords: antimicrobial peptides (AMPs); biomarkers; recurrent urinary tract infections (rUTI); urinary tract innate immunity; uroepithelial cell; urothelium; vitamin D deficiency.

FIGURE 1

PRISMA-flowchart (38) illustrating the literature search and study selection process.

FIGURE 2

Urothelial innate immunity mechanisms in defense against uropathogens. Uroepithelial cell detects uropathogen via pattern recognition receptors (TLR4). The triggered intracellular signaling cascade results in the activation of nuclear transcription factors (IRF3, IRF7, NF-kB) and ultimately leads to increased gene transcription, production and secretion of chemokines, cytokines and antimicrobial peptides into the urinary stream. Activation of TLR4 also leads to induction of COX-2 expression in the uroepithelial cell and, consequently, increased urinary PGE2. 25-hydroxy vitamin D from circulation converses to 1,25-dihydroxy vitamin D in urothelial cell by mitochondrial 1-α hydroxylase which is also induced by activated TLR4. Finally, 1,25-dihydroxy vitamin D binds to the vitamin D receptor in cytoplasm and translocates to the nucleus where it binds to the vitamin D responsive element and induces transcription of a potent antimicrobial peptide called cathelicidin. PAMP, pathogen associated molecular pattern; TLR, Toll-like receptor; IRF, interferon regulatory factor; NF-kB, nuclear factor kappa B; 25(OH)D, 25-hydroxy vitamin D; 1,25(OH)₂D, 1,25-dihydroxy vitamin D; VDR, vitamin D receptor; IL-8, interleukin 8; NGAL, neutrophil gelatinase associated lipocalin; NGF, nerve growth factor; G-CSF, granulocyte colony stimulating factor; SP-A, surfactant protein A; HNP1-3, human neutrophil peptides 1-3; COX-2, cyclooxigenase 2; PGE2, prostaglandin E2.