Impaired upper respiratory tract barrier function during postnatal development predisposes to invasive pneumococcal disease.

Autor: Kristen L Lokken-Toyli, Surya D Aggarwal, Gavyn Chern Wei Bee, Wouter A A de Steenhuijsen Piters, Cindy Wu, Kenny Zhi Ming Chen, Cynthia Loomis, Debby Bogaert, Jeffrey N Weiser
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: PLoS Pathogens, Vol 20, Iss 5, p e1012111 (2024)
Druh dokumentu: article
ISSN: 1553-7366
1553-7374
DOI: 10.1371/journal.ppat.1012111&type=printable
Popis: 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.
Databáze: Directory of Open Access Journals
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