ABSTRACT: Pathogen-Specific Alterations in Intestinal Microbiota Precede Urinary Tract Infections in Preterm Infants: A Longitudinal Case-Control Study
Project description:Pseudomonas aeruginosa is one of the most frequent pathogen dominant in complicated urinary tract infections (UTI). To unravel the adaptation strategies of P. aeruginosa to the conditions in the urinary tract and to define the underlying regulatory network an artificial growth system mimicking the conditions in the urinary tract was established. Transcriptome analyses were used to investigate the physiological status of P. aeruginosa under this conditions.
Project description:Staphylococcus (S.) epidermidis is one of the most common nosocomial coagulase-negative staphylococci infections in preterm infants. The clinical signs of infection are often unspecific and identification of novel markers to complement the current diagnosis is needed. In this study, we investigated proteomic alterations in the neonatal mouse brain following S. epidermidis infection and in the blood in preterm infants. We identified lipocalin 2 (LCN2) as a crucial protein associated with cerebrovascular changes and astrocyte reactivity in mice. While astrocytes were activated in S. epidermidis infected mice, LCN2 protein expression in the brain was associated with endothelial cells but not astrocyte reactivity. By combining weighted gene co-expression analysis and differential expression approaches, we further identified that LCN2 protein was linked to blood C-reactive protein levels in a cohort of preterm infants born <28 weeks of gestation. Blood LCN2 levels were associated with similar alterations of cytokines and chemokines in both infected mice and human preterm infants with increased levels of CRP. The present experimental and clinical study indicates that LCN2 might be a suitable additional marker of preterm infection/inflammation associated with cerebrovascular changes and neuroinflammation.
Project description:DNA methylation (DNAm) plays a determining role in neural cell fate and provides a molecular link between early life stress and life-course neuropsychiatric disease. Preterm birth is a profound environmental stressor that is closely associated with alterations in connectivity of neural systems and long-term neuropsychiatric impairment. The aims of this study were to examine the relationship between preterm birth and DNAm and to investigate factors that contribute to variance in DNAm. DNA was collected from preterm infants (birth < 32 weeks’ gestation) and healthy controls (birth > 37 weeks), and a genome-wide analysis of DNAm was performed; diffusion MRI (dMRI) data were acquired from the preterm group. The major fasciculi were segmented, and fractional anisotropy, mean diffusivity and tract shape were calculated. Principal components analysis was used to investigate the contribution of MRI features and key clinical variables to variance in DNAm. Differentially methylated regions were found within 25 gene bodies and 61 promoters of protein-coding genes in preterm infants compared with controls; 10 of these are associated with neural development or function. Differences detected in the array were validated with pyrosequencing. Ninety-five percent of the variance in DNAm in preterm infants was explained by 23 principal components (PC); corticospinal tract shape associated with 6th PC, and gender and early nutritional exposure associated with the 7th PC. Preterm birth is associated with alterations in the methylome at sites that influence neural development and function. The differentially methylated regions identified provide several promising candidate genes for understanding the genetic/epigenetic basis of preterm brain injury.
Project description:Proteus mirabilis is a leading cause of catheter-associated urinary tract infections (UTIs) and urolithiasis. The transcriptional regulator MrpJ inversely modulates two critical aspects of P. mirabilis UTI progression: fimbria-mediated attachment to the urinary tract, and flagella-mediated motility. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) was used for the first time in a CAUTI pathogen to probe for in vivo direct targets of MrpJ. ChIP-seq revealed 81 78 direct MrpJ targets, including genes for motility, fimbriae and a type VI secretion system (T6SS), and the putative MrpJ binding sequence ACnCnnnnnnnGnGT.
Project description:Analysis of influenza A and respiratory synctial virus infections in cultured nasal epithelial cells at the air-liquid interface (ALI) of adult, term, and preterm infants.
Project description:Urinary tract infections (UTIs) are the second most common infections encountered in the pediatric population, second only to respiratory tract infections. UTIs are also a major cause of morbidity and mortality. UTIs can often ascend causing infection in the upper urinary tract or even progress to bacteremia or urosepsis. Urosepsis accounts for 10-30% of septic shock cases and Uropathogenic E.coli (UPEC) is responsible for almost 75% of cases. Therefore, increased understanding of the effects of urosepsis at the cellular and organ specific level will provide the foundation for improvements in clinical care.