부산대학교 도서관

Infants are highly susceptible to invasive respiratory and gastrointestinal infections. To elucidate the age-dependent mechanism(s) that drive bacterial spread from the mucosa, we developed an infant mouse model using the prevalent pediatric respiratory pathogen, Streptococcus pneumoniae (Spn). Despite similar upper respiratory tract (URT) colonization levels, the survival rate of Spn-infected infant mice was significantly decreased compared to adults and corresponded with Spn dissemination to the bloodstream. An increased rate of pneumococcal bacteremia in early life beyond the newborn period was attributed to increased bacterial translocation across the URT barrier. Bacterial dissemination in infant mice was independent of URT monocyte or neutrophil infiltration, phagocyte-derived ROS or RNS, inflammation mediated by toll-like receptor 2 or interleukin 1 receptor signaling, or the pore-forming toxin pneumolysin. Using molecular barcoding of Spn, we found that only a minority of bacterial clones in the nasopharynx disseminated to the blood in infant mice, indicating the absence of robust URT barrier breakdown. Rather, transcriptional profiling of the URT epithelium revealed a failure of infant mice to upregulate genes involved in the tight junction pathway. Expression of many such genes was also decreased in early life in humans. Infant mice also showed increased URT barrier permeability and delayed mucociliary clearance during the first two weeks of life, which corresponded with tighter attachment of bacteria to the respiratory epithelium. Together, these results demonstrate a window of vulnerability during postnatal development when altered mucosal barrier function facilitates bacterial dissemination. Author summary: In children, bacterial respiratory and gastrointestinal pathogens remain major contributors to childhood mortality worldwide. Yet, the immune deficiencies intrinsic to early age that compromise bacterial control during infection remain relatively unknown. In this study, we utilized clinically relevant infant mouse models and a human newborn study to characterize mucosal barrier defenses that are critical for mediating resistance to invasive infection. Using the prominent pediatric respiratory pathogen, Streptococcus pneumoniae (Spn), we show that the postnatal period is associated with an increased susceptibility to invasive Spn infection following nasal colonization. In contrast to adult mice, infant mice exhibited increased bacterial translocation across the nasal mucosal barrier that was independent of robust barrier damage. Instead, transcriptional analysis of the nasal epithelium in infant mice revealed decreased expression of tight junction proteins that corresponded with increased barrier permeability and delayed mucociliary clearance. Strikingly, a similar transcriptional signature was also observed in nasopharyngeal samples collected from human infants during the first year of life. These findings suggested that disruption in barrier integrity and function may be a hallmark of postnatal development. Collectively, our data underscores a vulnerable period during early life when impaired nasal barrier defenses facilitate bacterial translocation, culminating in invasive infection. [ABSTRACT FROM AUTHOR]