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Abstract: Preterm infants are uniquely susceptible to late‐onset sepsis that is frequently caused by the skin commensal Staphylococcus epidermidis. Innate immune responses, particularly from monocytes, are a key protective mechanism. Impaired cytokine production by preterm infant monocytes is well described, but few studies have comprehensively assessed the corresponding monocyte transcriptional response. Innate immune responses in preterm infants may be modulated by inflammation such as prenatal exposure to histologic chorioamnionitis which complicates 40–70% of preterm pregnancies. Chorioamnionitis alters the risk of late‐onset sepsis, but its effect on monocyte function is largely unknown. Here, we aimed to determine the impact of exposure to chorioamnionitis on the proportions and phenotype of cord blood monocytes using flow cytometry, as well as their transcriptional response to live S. epidermidis. RNA‐seq was performed on purified cord blood monocytes from very preterm infants (<32 weeks gestation, with and without chorioamnionitis‐exposure) and term infants (37–40 weeks), pre‐ and postchallenge with live S. epidermidis. Preterm monocytes from infants without chorioamnionitis‐exposure did not exhibit an intrinsically deficient transcriptional response to S. epidermidis compared to term infants. In contrast, chorioamnionitis‐exposure was associated with hypo‐responsive transcriptional phenotype regarding a subset of genes involved in antigen presentation and adaptive immunity. Overall, our findings suggest that prenatal exposure to inflammation may alter the risk of sepsis in preterm infants partly by modulation of monocyte responses to pathogens. [ABSTRACT FROM AUTHOR]

Escherichia coli and Staphylococcus epidermidis are predominant causes of neonatal sepsis, particularly affecting preterm infants. Susceptibility to infection has been attributed to 'immature' innate monocyte defences, but no studies have assessed global transcriptional responses of neonatal monocytes to these pathogens. Here, we aimed to identify and characterise the neonatal monocyte transcriptional responses to E. coli and S. epidermidis and the role of common modifiers such as gestational age (GA) and exposure to chorioamnionitis (a common complication of preterm birth) to better understand early life innate immune responses. RNA-sequencing was performed on purified cord blood monocytes from very preterm (< 32 weeks GA) and term infants (37-40 weeks GA) following standardised challenge with live S. epidermidis or E. coli. The major transcriptional changes induced by either pathogen were highly conserved between infant groups and stimuli, highlighting a common extant neonatal monocyte response to infection, largely mediated by TLR/NF-κB/TREM-1 signalling. In addition, we observed an activated interferon-centred immune response specific to stimulation with E. coli in both preterm and term infants. These data provide novel insights into the functionality of neonatal monocytes at birth and highlight potential pathways that could be targeted to reduce the harmful effects of bacterial-induced inflammation in sepsis. E. coli and S. epidermidis elicit common transcriptional changes in cord monocytes. The common transcriptional response is mediated by TLR/NF-κB/TREM-1 signalling. IFN genes are differentially regulated by E. coli and S. epidermidis in monocytes. These responses are largely unaffected by GA or exposure to chorioamnionitis. Key messages: [ABSTRACT FROM AUTHOR]

Aim To evaluate mononuclear cell expression and function of the cytosolic nucleotide-binding oligomerization domain-containing receptors, NOD1 and NOD2, in very preterm and full-term infants. Methods NOD1 and NOD2 gene and protein expression in very preterm infants, term infants and healthy adult, cord and peripheral blood mononuclear cells (C/ PBMC) were quantified using q PCR and flow cytometry. Cytokine responses of purified infant and adult monocytes to NOD1- and NOD2-specific agonists were assessed using a multiplex immunoassay (Bioplex). Results NOD1 and NOD2 were expressed by a range of infant and adult mononuclear cell types, including T- and B cells, with highest expression in classical ( CD14++ CD16−) and intermediate ( CD14++ CD16+) monocytes. NOD1 and NOD2 expression levels by monocytes from very preterm infant were similar to those in term infants or adults. Monocyte production of TNF α, IL-6 and IL-1 β induced by activation of NOD1 and NOD2 was similar between very preterm infants, term infants and adults. Conclusion Monocyte expression and function of NOD1 and NOD2 in very preterm infants are intact and comparable/equivalent to term infants and adults. Functional deficiencies in monocyte NOD signalling pathways are unlikely to contribute to the increased susceptibility to bacterial sepsis in preterm infants. [ABSTRACT FROM AUTHOR]