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Transcriptome-wide profiling of the neonatal monocyte response to E. coli and S. epidermidis

de Jong, Emma (2015) Transcriptome-wide profiling of the neonatal monocyte response to E. coli and S. epidermidis. PhD thesis, Murdoch University.

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Preterm infants are extremely vulnerable to life-threatening invasive infections (particularly with Staphylococcus epidermidis and Escherichia coli) however our understanding of their innate immune defences is limited. Furthermore, prenatal exposure to histologic chorioamnionitis (HCA) complicates 40–70% of preterm births and is known to modulate the risk for sepsis, yet the impact of HCA on the development of innate immunity is largely unknown. We hypothesised that inadequate monocyte activation by neonatal pathogens results in impaired innate immune responses thereby increasing preterm infants’ susceptibility to invasive infection, and that prenatal exposure to HCA overrides these impairments.

Cell sorting and bacterial stimulation methodologies were developed and optimised specifically for working with human infant cord blood samples. RNA-sequencing was performed on purified cord blood monocytes from very preterm (≤31 weeks gestational age (GA)) and term infants (37–40 weeks GA) following challenge with live S. epidermidis or E. coli to identify gene/pathway differences specific to the preterm infant. Protein levels of inflammatory cytokines and chemokines were measured in paired monocyte culture supernatants.

Preterm infants displayed a quantitative monocyte deficiency compared to term infants, manifesting as reduced frequencies of classical monocytes with significantly reduced CD14 expression. However monocytes from preterm infants did not exhibit an intrinsically deficient transcriptional or protein response to stimulation with either pathogen. Prenatal exposure to HCA resulted in the transcriptional reprograming of a subset of genes towards a hyporesponsive phenotype in response to S. epidermidis, but not E. coli. The major transcriptional changes induced by either pathogen were highly conserved across infant groups and between stimuli, highlighting a conserved neonatal monocyte response to infection that was largely mediated by pattern recognition receptor/NF-kB signalling. In addition, we observed an interferon/anti-viral immune signature that was specific to monocyte stimulation with E. coli.

This is the first transcriptome-wide analysis of the neonatal monocyte response to E. coli and S. epidermidis. This data provides novel insights into the functionality of preterm and term infant monocytes and confirms that exposure to HCA may impact on the development on neonatal immunity.

Item Type: Thesis (PhD)
Murdoch Affiliation(s): School of Veterinary and Life Sciences
Supervisor(s): Currie, Andrew, Strunk, Tobias and Richmond, Peter
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