Studies on Variations in Host Gene Defect and Functional Expression Difference Associated with Inflammasome-Dependent Innate Immunity among Pediatric Patients with Different Severe Renal Infections

Urinary tract infections (UTIs) have been described as one of the most common bacterial infections affecting infants and young children. Approximately 3% of prepubertal girls and 1% of prepubertal boys are diagnosed with UTIs. The clinical severity of acute renal bacterial infection spans continuously from asymptomatic bacteriuria, uncomplicated lower UTI to frank abscess formation. Acute lobar nephronia (ALN) has been diagnosed with increasing frequency due to the advancement of non-invasive imaging modalities. It has been indicated as a complicated form of acute renal infection, representing the progression of the inflammatory process of acute pyelonephritis (APN). ALN may also represent a relatively early stage of the development of renal abscess. The incidence rate of ALN is 8-10% among Taiwanese children with a febrile UTI.Our previous studies have indicated that the papG II allele was the only significant urovirulence factor associated with ALN. Nevertheless, the intra-individual differences in clinical presentations remains noted when patients are infected with same uropathogenic E. coli genes. This underlies the importance of host factors, such as SNPs in genes modulating innate immune responses against bacterial infections, in patient’s susceptibility to UTIs.Among various innate immunity responses, the toll-like receptor (TLRs)-dependent innate immunity has been implicated to play specific pathogenic roles against UTIs. Our previous investigations have revealed that the genetic variations in interleukin-8 could confer increase susceptibility in severe renal parenchymal infections (i.e. ALN). In contrast, genetic polymorphisms in Toll-like receptor 2 are linked to the host protection for severe renal infections. Despite of these efforts, issues regarding the bacterial infections caused by the intracellular microbes still unanswered since TLRs are only either expressed at the cell membrane or at endosomal membranes. This implicates the importance of inflammasome-dependent innate responses which are initiated by the family of nucleotide-binding oligomerization domain (NOD) proteins in detecting pathogens in the cytosol of host cells (e.g. intracellular bacterial communities; IBCs).The likely linkage of inflammasome-dependent innate immunity with the urinary tract infections are not demonstrated until our SNPs analyses on pediatric severe renal parenchymal infections (2015) and the lower UTI animal model by Waldhuber et al. (2016). Despite of these, various issues regarding the roles of inflammasome-dependent innate immunity on various severe renal bacterial infections remain unanswered. Henceforth, based upon our 2016 results, we propose to further examine the pathogenic correlations of inflammasome-dependent innate immunity with pediatric severe UTIs by evaluating the genetic variations and functional differences in genes modulating the inflammasome-dependent innate immune pathways among children with severe renal parenchymal infections, namely the patients with ALN, APN, recurrent severe UTIs after previous APN or ALN attack, and renal scarring following the ALN or APN. Through these studies, we will expect to have a better pathogenic understanding about the roles of various host factors among pediatric patients with severe urinary tract infections. In addition, the genetic and functional studies proposed here to examine the individual susceptibility could likely serve as a new tool for future risk assessment in these severe renal infection patient groups.

Project ID:PC10708-0970
External Project ID:MOST107-2314-B182-043