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|Title:||The Regulation of the Innate Immune System in Preterm Neonates|
|School/Discipline:||Adelaide Medical School|
|Abstract:||Preterm delivery is the leading contributor to neonatal death globally, with half of these deaths being associated with inflammatory conditions. An immature ability to regulate the innate immune response may contribute to the higher rate of morbidity and mortality among preterm neonates. Neonates rely on their innate immune response to protect them from infection. Toll-like receptors (TLRs) are ubiquitously expressed innate immune receptors that signal for pro-inflammatory cytokine transcription. This process requires strict regulation at different levels of its intracellular signalling cascade to avoid pathological inflammation. MicroRNAs (miRs) are post-transcriptional regulators that have been identified as critical regulators of inflammatory gene expression. Currently, miR expression is sparsely characterised in the context of neonatal TLR signalling. This thesis therefore aimed to examine immune regulation by term and preterm neonates through characterising the expression of miRs that regulate TLR signalling in placenta and cord blood. Cord blood and placenta were collected following term (≥ 37 weeks gestation), late preterm (32-36 weeks) and early preterm delivery (≤ 32 weeks), and assessed for baseline gene expression (Chapters 3 and 4). Cord blood was cultured and stimulated with TLR2, TLR3 and TLR4 agonists, and collected over a 24 hour period (Chapters 5 and 6). RNA was extracted and the relative expression of genes associated with TLR signalling (including select miRs) was quantified using qPCR. Bioinformatics analyses were used to determine network-level alterations in inflammatory signalling using publicly available microarray data on peripheral blood from neonates with infection (Chapter 7). There was no difference in the expression of miRs or genes associated with TLR signalling in the placenta or cord blood between term and late preterm deliveries. Early preterm cord blood showed decreased miR-155 and let-7e expression at birth, and demonstrated no change in miR expression following TLR stimulation despite increasing the expression of IL6, IL10 and NF-κB1. Term and late preterm cord blood also increased IL6 expression, but this occurred alongside increased anti-inflammatory let-7e expression. Further, term cord blood increased TNFα and IL6 protein production until 6 hours in vitro, while preterm cord blood continued to increase IL6 between 6 and 24 hours post-stimulation. Bioinformatics analysis confirmed an upregulation of innate immune pathways (including JAK-STAT and Nod-like Receptor signalling) in peripheral blood from preterm neonates with infection compared to term neonates with infection. In summary, our findings demonstrate preterm cord blood is able to mount a robust response to TLR stimulation through increasing pro-inflammatory gene expression. As this response occurs in the absence of any change in the miRs we measured, we postulate that the inflammatory response is dysregulated in preterm neonates. These results are the first to suggest differential miR expression alters the neonatal innate immune response. As such, in addition to an increased risk of contracting infection, preterm neonates may be unable to regulate inflammation effectively. Inappropriate inflammatory signalling may therefore underlie preterm neonates’ susceptibility to developing chronic and acute inflammatory morbidities.|
|Dissertation Note:||Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2018|
|Provenance:||This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals|
|Appears in Collections:||Research Theses|
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