Emma de Jong
Transcriptome-wide profiling of the neonatal monocyte response to invasive pathogens.
The preterm population accounts for 75% of all neonatal morbidity/mortality in high-resource countries. This vulnerability is largely due to invasive infections during the neonatal period. Importantly, susceptibility to infection is inversely correlated with gestational age, suggesting there are critical deficiencies in the innate immune pathways of preterm infants required for control of invasive neonatal pathogens. Our understanding of these immune deficiencies is limited. However recent work by our group suggests that inadequate monocyte activation may result in reduced pathogen-induced responses in preterm cord blood, compared with term infant and adult responses. My thesis aims to characterise the protective human monocyte responses to two neonatal pathogens (Staphylococcus epidermidis, Escherichia coli) and identify gene/pathway deficiencies specific to the preterm infant. Transcriptomics (RNA-seq) is being performed on purified (>90%) cord blood monocytes following stimulation with live S. epidermidis or E. coli. Five biological replicates from each group (preterm, term) are included to ensure sufficient statistical power to identify the majority of differentially expressed transcripts. Culture supernatant is being collected in parallel for cytokine/chemokine analysis. Successful mapping of monocyte genes/pathways required for control of invasive neonatal pathogens will greatly enhance our understanding of the immunological mechanisms underlying susceptibility to infection in preterm infants.
Why my research is important
Infants born prematurely, especially those born more than 8 weeks too early, are very prone to serious infections in the first few weeks of life. In particular, they’re at risk of infections with bacteria called Escherichia coli and Staphylococcus epidermidis. However, we still don’t know why these preterm infants can’t defend themselves against these bacteria, or even how healthy, full-term infants manage to control infection. Recent findings from studies of the immune system have suggested that our inborn (innate) immune defences are critical for preventing bacterial infections, but there is little information on the function of these defences in infants. In this study we will use sophisticated molecular tools to determine which immune responses are absolutely needed to control E. coli and S. epi infections in neonates.
These tools allow us to measure the responses of all 22,000 human genes to bacterial challenge at one time. By comparing the pattern of gene responses in newborns at high risk of infection (those born prematurely) and low risk of infection (born at full term), we believe that we will identify the specific set of genes required to control E. coli and S. epi infections. Identifying the most important defence genes will give us a powerful tool for potentially predicting which infants (preterm or otherwise) are at most risk of infections. Knowing this would pave the way for new treatments that can reduce infections, or even prevent them in the first place.