Studies of Neutrophil-Dependent Innate Immune Pathways among the Children with Various Severe Urinary Tract Infections

Urinary tract infections (UTIs) have been described as one of the most common bacterial diseases 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), a localized nonliquefactive inflammatory renal bacterial infection, has been diagnosed with ever-increasing frequency in patients, due to the advancement of non-invasive imaging-technique modalities. It has previously 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 study has indicated that, among the pathogenic urovirulent genes examined, a 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 single gene defects or variations in genes modulating innate immune responses for bacterial clearance and elimination, in patient’s susceptibility to the bacterial invasion and infection. Due to simpler living habits as compared to the adults, the pediatric patients are commonly employed as the clinical model for studying the likely host effects on clinical severity of urinary tract infections. Among various innate immune defense responses, the neutrophil-dependent one is considered to be the most important process to defend bacterial UTIs. Our latest investigations have revealed that the genetic variations in interleukin-8 of the neutrophil-dependent innate immune pathway 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. This investigation is aimed to extend our previous efforts in determining the likely genetic variations and functional differences in genes modulating the neutrophil-dependent innate immune pathways among the children with severe renal parenchymal infections, namely patients with ALN, APN, recurrent severe UTIs after previous APN or ALN attack, and renal scarring following ALN or APN renal parenchymal infections. In addition to examine the possible genetic and functional expression variations in the CXCR1 (IL-8 receptor), IL-8, TLR-1 (Toll-like receptor 1), TLR-2, TLR-4, TLR-5, and TLR-6 among these severe infected patients, we also extend our research to examine the likely genetic and functional differences in a novel gene, IRF3, that regulates the transcription of Toll-like receptors during uropathogen attacks. Through these studies, we will expect to have a better pathogenic understanding about the roles of various host factors among these pediatric with severe urinary tract infectious diseases. 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:PC10308-0646
External Project ID:MOST103-2314-B182-022-MY3