Genetic Polymorphisms in Toll-Like Receptors among Pediatric Patients with Renal Parenchymal Infections of Different Clinical Severities

Chi-Hui Cheng,Tzou-Yien Lin,Chee-Jen Chang,Yun-Shien Lee,Ashok Kumar

doi:10.1371/journal.pone.0058687

Abstract

BackgroundAlthough several studies have suggested single gene defects or variations in the genes associated with host immune response could confer differences in susceptibility to urinary pathogen invasion, no studies have examined the genetic polymorphisms in various toll-like receptors (TLRs) that activate innate immune responses in pediatric renal parenchymal infections of different clinical severities, namely acute pyelonephritis and the clinically more severe disease, acute lobar nephronia.MethodologyPatients who fulfilled the diagnostic criteria for acute pyelonephritis (APN) and acute lobar nephronia (ALN) without underlying diseases or structural anomalies, except for vesicoureteral reflux (VUR), were enrolled. Genotyping of the single nucleotide polymorphisms (SNPs) in the genes encoding TLR-1, TLR-2, TLR-4, TLR-5, and TLR-6 was performed by matrix-assisted laser desorption/ionization time-of-flight-based mini-sequencing analysis.Principal FindingsA total of 16 SNPs were selected for genotyping. Analysis of 96 normal and 48 patients’ samples revealed that only four SNPs had heterozygosity rates >0.01. These SNPs were selected for further investigation. Hardy-Weinberg equilibrium was satisfied for the observed genotype frequencies. Statistically significant differences in the genotype frequency of TLR-2 (rs3804100, T1350C) between controls and ALN or (APN+ALN) combined group were identified using the recessive model with the correction for multiple-SNP testing. Further genotype pattern frequency analysis in TLR-2 SNPs (rs3804099 and rs3804100) showed significantly reduced occurrence of the rare allele homozygote (CC+CC) in the no-VUR subgroup of APN and ALN cases.ConclusionsAs the inflammatory responses in ALN patients are more severe than those in APN patients (higher CRP levels, longer duration of fever after antibiotic treatment), these findings suggest that the genetic variant in TLR-2 (rs3804100, T1350C) may protect the host from severe urinary tract infections as ALN.

Highlights

Urinary tract infections (UTIs) are among the most prevalent infectious bacterial diseases in infants and children
As the inflammatory responses in acute lobar nephronia (ALN) patients are more severe than those in acute pyelonephritis (APN) patients, these findings suggest that the genetic variant in toll-like receptors (TLRs)-2 may protect the host from severe urinary tract infections as ALN
To extend our previous analysis of genetic polymorphisms in pediatric patients with renal parenchymal infections [12], this study explored the correlations between polymorphisms in UTI

Summary

Introduction

Urinary tract infections (UTIs) are among the most prevalent infectious bacterial diseases in infants and children. Among the UTIs, acute lobar nephronia (ALN), known as acute focal bacterial nephritis, presents as a localized nonliquefactive inflammatory renal bacterial infection and has previously been identified as a complicated form of acute renal infection, representing progression of the inflammatory process of acute pyelonephritis (APN) [2]. It is generally accepted that renal parenchymal infections, including APN, ALN, and intrarenal abscess formation, are the more serious forms of UTI and have a longer duration of antibiotic treatment. Several studies have suggested single gene defects or variations in the genes associated with host immune response could confer differences in susceptibility to urinary pathogen invasion, no studies have examined the genetic polymorphisms in various toll-like receptors (TLRs) that activate innate immune responses in pediatric renal parenchymal infections of different clinical severities, namely acute pyelonephritis and the clinically more severe disease, acute lobar nephronia

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