Genetic Polymorphisms in Inflammasome-Dependent Innate Immunity among Pediatric Patients with Severe Renal Parenchymal Infections

Abstract

BackgroundInflammasome innate immune response activation has been demonstrated in various inflammatory diseases and microbial infections. However, to our knowledge, no study has examined the inflammasome-dependent pathways in patients with urinary tract infection. Defective or variant genes associated with innate immunity are believed to alter the host’s susceptibility to microbial infection. This study investigated genetic polymorphisms in genes encoding inflammasomes and the subsequent released cytokines in pediatric patients with severe renal parenchymal infections.MethodologyThis study included patients diagnosed with acute pyelonephritis (APN) and acute lobar nephronia (ALN) who had no underlying disease or structural anomalies other than vesicoureteral reflux (VUR). Single nucleotide polymorphism (SNP) genotyping was performed in the genes associated with inflammasome formation and activation (NLRP3, CARD8) and subsequent IL–1β cytokine generation (IL–1β).Principal FindingsA total of 40 SNPs were selected for initial genotyping. Analysis of samples from 48 patients each and 96 controls revealed that only nine SNPs (five SNPs in NLRP3; three SNPs in CARD8; one SNP in IL–1β) had heterozygosity rates >0.01. Hardy–Weinberg equilibrium was satisfied for the observed genotype frequencies of these SNPs. Analysis excluding patients with VUR, a well-known risk factor for severe UTIs, revealed a lower frequency of the CC genotype in NLRP3 (rs4612666) in patients with APN and ALN than in controls. Correction for multiple-SNP testing showed that the non-VUR subgroup of the APN+ALN combined patient groups remained significantly different from the control group (P < 0.0055).ConclusionsThis study is the first to suggest that the inflammasome-dependent innate immunity pathway is associated with the pathogenesis of pediatric severe renal parenchymal infections. Further investigation is warranted to clarify its pathogenic mechanism.

Mitochondrial antiviral signaling protein: a potential therapeutic target in renal disease

“…Mounting evidence indicates that NLRP3 has important effects on several kidney diseases, including pyelonephritis ( 75 ) and IgA nephropathy ( 76 ). These reports indicate that MAVS and its downstream factor, NLRP3, play diverse roles in renal disease by stimulating inflammation, renal tubular epithelial cell injury, apoptosis, epithelial-mesenchymal transition, and tubulointerstitial fibrosis.…”

Acute Lobar Nephronia Secondary to Obstruction Due to Urolithiasis*

“…Other than crystalluria, genetical polymorphisms in inflammasome-dependent innate immunity and toll-like receptors may be responsible for ALN development. [9][10][11] As ALN produces a mass lesion that may mimic other entities, diagnosis is important for sufficient antibiotic treatment and avoidance of unnecessary invasive operations.…”

Genetic Polymorphisms ofIL1B, IL6,andTNFαin a Chinese Han Population with Pulmonary Tuberculosis

“…Several cytokine gene polymorphisms have been reported to affect gene transcription and influence serum cytokine production [ 8 , 9 ]. Polymorphisms in cytokine gene have been suggested to play key roles in the susceptibility, development, and severity of infectious diseases [ 10 ]. Among the inflammatory cytokine genes, IL1B , IL6 , and TNFα were demonstrated to be associated with TB infection or TB disease [ 11 – 13 ].…”