Decreased production of epithelial-derived antimicrobial molecules at mucosal barriers during early life

Abstract

Young age is a risk factor for respiratory and gastrointestinal infections. Here, we compared infant and adult mice to identify age-dependent mechanisms that drive susceptibility to mucosal infections during early life. Transcriptional profiling of the upper respiratory tract (URT) epithelium revealed significant dampening of early life innate mucosal defenses. Epithelial-mediated production of the most abundant antimicrobial molecules, lysozyme and lactoferrin, and the polymeric immunoglobulin receptor (pIgR), responsible for IgA transcytosis, was expressed in an age-dependent manner. This was attributed to delayed functional development of serous cells. Absence of epithelial-derived lysozyme and the pIgR was also observed in the small intestine during early life. Infection of infant mice with lysozyme-susceptible strains of Streptococcus pneumoniae or Staphylococcus aureus in the URT or gastrointestinal tract, respectively, demonstrated an age-dependent regulation of lysozyme enzymatic activity. Lysozyme derived from maternal milk partially compensated for the reduction in URT lysozyme activity of infant mice. Similar to our observations in mice, expression of lysozyme and the pIgR in nasopharyngeal samples collected from healthy human infants during the first year of life followed an age-dependent regulation. Thus, a global pattern of reduced antimicrobial and IgA-mediated defenses may contribute to increased susceptibility of young children to mucosal infections.

Silent neonatal influenza A virus infection primes systemic antimicrobial immunity

“…Profound changes in the respiratory microbiota during the first days of life have a strong impact on immune maturation processes during this period, particularly on anti-viral immunity ( 44 – 46 ). Furthermore, multiple studies provided evidence for specific immune maturation processes during the first 2 weeks of a mouse life, such as increased epithelial production of antimicrobial peptides ( 47 ), DC functions ( 48 , 49 ), frequency of lung resident T cells ( 50 ) and AMs ( 51 ), and advanced Th1 differentiation ( 48 , 52 ). Considering that S. aureus is the leading cause of infection in the setting of critical illness and injury, our finding of enhanced anti- S. aureus immunity after neonatal IAV exposure might add an important argument to the research area of neonatal vaccinology.…”

Antimicrobial peptides modulate lung injury by altering the intestinal microbiota

“…Forced oscillometry: A subset of P14 mice not used for morphometry or transcriptomics were sedated with ketamine and xylazine via I.P. injection, and the flexiVent system (SCIREQ) was used to assess respiratory resistance and compliance as described (15,17). Briefly, the mice were tracheotomized with the appropriately sized cannula secured with a silk ligature.…”

“…Having shown that exposure to supraphysiologic oxygen resulted in depressed expression of intestinal AMPs and an altered microbiome, we next wanted to test if AMP expression drove this effect. Lysozyme is the principal AMP, and expression is reduced in early life on most mucosal surfaces 15 . To test if the suppression of AMP expression in hyperoxia-exposed mice might have functional consequences, we repeated the hyperoxia-exposure experiment above using nearly genetically identical mice (C57BL/6NCrl, Figure 3A).…”

Host Defense Peptides in Nutrition and Diseases: A Contributor of Immunology Modulation

“…A rich repertoire of HDPs is distributed widely in animals, particularly in the mucous epithelium of the digestive tract, respiratory tract, genital tract, skin, and immune cells, which easily contact microorganisms. Accumulating data have shown that the differences in endogenous HDP expression are age-dependent, species-dependent, and tissue-dependent − (Table ). HDP expression is either constitutive or induced, and the pattern is quite varied and complex.…”