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Lower respiratory tract infections (LRTIs) remain the leading cause of infant morbidity and mortality worldwide and affect long-term respiratory health. Identifying immunological determinants of LRTI susceptibility may help stratify disease risk and identify therapies. This study aimed to identify neonatal immunological factors predicting LRTI risk in infancy. Cord blood plasma from 191 neonates from the Boston Birth Cohort was analyzed for 28 soluble immune factors. LRTI was defined as bronchiolitis, bronchitis, or pneumonia during the first year of life. Welch's t -test demonstrated significantly higher log 10 transformed concentrations of IL-17 and IFNγ in the LRTI group compared to neonates without LRTI in the first year of life ( p < 0.05). Risk associations were determined using multivariate survival models. There were 29 infants with LRTIs. High cord blood levels of IFNγ (aHR = 2.35, 95% CI 1.07-5.17), TNF-β (aHR = 2.86, 95% CI 1.27-6.47), MIP-1α (aHR = 2.82, 95% CI 1.22-6.51), and MIP-1β (aHR = 2.34, 95% CI 1.05-5.20) were associated with a higher risk of LRTIs. RANTES was associated with a lower risk (aHR = 0.43, 95% CI 0.19-0.97). Soluble immune factors linked to antiviral immunity (IFNγ) and cytokines mediating inflammatory responses (TNF-β), and cell homing (MIP-1α/b), at birth were associated with an increased risk of LRTIs during infancy.

Over the past two decades, several studies have positioned early-life microbial exposure as a key factor for protection or susceptibility to respiratory diseases. Birth cohorts have identified a strong link between neonatal bacterial colonization of the nasal airway and gut with the risk for respiratory infections and childhood asthma. Translational studies have provided companion mechanistic insights on how viral and bacterial exposures in early life affect immune development at the respiratory mucosal barrier. In this review, we summarize and discuss our current understanding of how early microbial-immune interactions occur during infancy, with a particular focus on the emergent paradigm of "innate immune training". Future human-based studies including newborns and infants are needed to inform the timing and key pathways implicated in the development, maturation, and innate training of the airway immune response, and how early microbiota and virus exposures modulate these processes in the respiratory system during health and disease.

DNA methylation (DNAm) is an essential mechanism governing normal development in humans. Although most DNAm patterns in blood cells are established in utero , the genes associated with immune function undergo postnatal DNAm modifications, and the characterization of this subset of genes is incomplete. Accordingly, we used available longitudinal DNAm datasets from a large birth cohort in the U.S. to further identify postnatal DNAm variation in peripheral leukocytes from 105 children ( n = 105) between birth and the first two years of life, as determined by postnatal changes in β values (with the percentage of methylation ranging from 0 to 1.0 at individual CpG sites). Our study is an extension of a previous analysis performed by our group and identified that: (1) as previously described, DNAm patterns at most CpG sites were established before birth and only a small group of genes underwent DNAm modifications postnatally, (2) this subset includes multiple immune genes critical for lymphocyte development, and (3) several members of the tumor necrosis factor receptor and cytokine superfamilies with essential roles in immune cell activation, survival, and lymphoid tissue development were among those with a larger postnatal variation. This study describes the precise epigenetic DNA methylation marks in important immune genes that change postnatally and raises relevant questions about the role of DNAm during postnatal immune development in early childhood., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.