Toll-like receptors (TLRs) are crucial transmembrane receptors that form part of the innate immune response. They play a role in the recognition of various microorganisms and their elimination from the host. TLRs have been proposed as vital immunomodulators in the regulation of multiple neonatal stressors that extend beyond infection such as oxidative stress and pain. The immune system is immature at birth and takes some time to become fully established. As such, babies are especially vulnerable to sepsis at this early stage of life. Findings suggest a gestational age-dependent increase in TLR expression. TLRs engage with accessory and adaptor proteins to facilitate recognition of pathogens and their activation of the receptor. TLRs are generally upregulated during infection and promote the transcription and release of proinflammatory cytokines. Several studies report that TLRs are epigenetically modulated by chromatin changes and promoter methylation upon bacterial infection which have long-term influences on immune responses. TLR activation is reported to modulate cardiorespiratory responses during infection and may play a key role in driving homeostatic instability observed during sepsis. Although complex, TLR signalling and downstream pathways are potential therapeutic targets in the treatment of neonatal diseases. By reviewing the expression and function of key toll-like receptors, we aim to provide an important framework to understand the functional role of these receptors in response to stress and infection in premature infants.

Prematurity is the leading cause of neonatal morbidity and mortality worldwide. Premature infants often require extended hospital stays, with increased risk of developing infection compared with term infants. A picture is emerging of wide-ranging deleterious consequences resulting from innate immune system activation in the newborn infant. Those who survive infection have been exposed to a stimulus that can impose long-lasting alterations into later life. In this review, we discuss sepsis-driven alterations in integrated neuroendocrine and metabolic pathways and highlight current knowledge gaps in respect of neonatal sepsis. We review established biomarkers for sepsis and extend the discussion to examine emerging findings from human and animal models of neonatal sepsis that propose novel biomarkers for early identification of sepsis. Future research in this area is required to establish a greater understanding of the distinct neonatal signature of early and late-stage infection, to improve diagnosis, curtail inappropriate antibiotic use and promote precision medicine through a biomarker-guided empirical and adjunctive treatment approach for neonatal sepsis. There is an unmet clinical need to decrease sepsis-induced morbidity in neonates, to limit and prevent adverse consequences in later life and decrease mortality.

silencing by early-life hypoxic stress programmes respiratory motor control. Experimental Physiology.

Preterm infant immaturity is characterised by unstable cardiorespiratory control, with male infants exhibiting poorer clinical outcomes. Very/Extremely preterm infants are at an increased risk of infection in early life. Infections are often caused by Gram‐positive bacteria that activate inflammatory pathways. We sought to characterise respiratory function and redox status in response to early life oxygen dysregulation (intermitted hypoxia and hyperoxia) and subsequent immune challenge using gram positive bacterial proteins. This study was approved by local animal ethics committee and the national regulatory body, HPRA Ireland. On postnatal day (PND) three, Sprague Dawley litters were exposed for 10 days to either cIHH or sham conditions. Following intraperitoneal (i.p) administration of LTA+PGN or vehicle solution on PND13, animals were monitored for 3 hours using whole body plethysmography. VCO2 was measured in parallel. A separate cohort of animals were exposed to an autoresuscitation protocol which consisted of acute anoxia until primary gasp and subsequent recovery in normoxic conditions (FiO2 21%). In littermates exposed to either cIHH/Sham and subsequent LTA+PGN/vehicle administration, blood, plasma and tissue was collected post‐mortem. Blood (pH and lactate) analysis was performed, plasma cortisol concentrations were quantified, and mRNA expression of NAD(P)H Quinone Dehydrogenase 1 was quantified in the diaphragm muscle. All data were analysed using a three‐way ANOVA (factors: sex, gas, drug), n=8‐10. There was a small decrease in the ventilatory equivalent following cIHH exposure (gas P<0.05). However, there was no evidence of acid‐base disturbance. We observed increased number of sighs in cIHH treated female animals (gas x sex P<0.05). NQO1 mRNA expression was upregulated in both sexes following cIHH gas exposure (gas factor P<0.05), most evident in males. Post‐sigh apnoea duration was decreased following immune challenge in both male and female rats (P<0.05). Cortisol concentrations were upregulated in both males and females following immune challenge (drug P<0.05 and sex x drug P<0.05), with higher expression evident in males. Primary apnoea duration in response to anoxia was similar across all groups. Although total number of gasps in the 30seconds post primary apnoea was significantly increased in sham females that received LTA&PGN (gas x drug interaction P<0.05). Gasping was significantly decreased in cIHH exposed females. cIHH upregulation of the anti‐oxidant pathway likely protects against oxidative stress and inflammation. cIHH also enhanced the number of sighs, known to be important in homeostatically regulating breathing variability. Neonatal exposure to immune challenge potently increased the stress hormone cortisol and increased post‐anoxic gasping in control conditions. This research has also revealed interesting sex‐specific effects as well as interactions between neonatal oxygen dysregulation and a subsequent immune challenge that need to be explored further.