An Immunological Perspective on Neonatal Sepsis

Abstract

Despite concerted international efforts, mortality from neonatal infections remains unacceptably high in some areas of the world, particularly for premature infants. Recent developments in flow cytometry and next-generation sequencing technologies have led to major discoveries over the past few years, providing a more integrated understanding of the developing human immune system in the context of its microbial environment. We review these recent findings, focusing on how in human newborns incomplete maturation of the immune system before a full term of gestation impacts on their vulnerability to infection. We also discuss some of the clinical implications of this research in guiding the design of more-accurate age-adapted diagnostic and preventive strategies for neonatal sepsis.

Keywords: fetal development; immunology; neonate; ontogeny; systems biology.

Figure 1. Immune Development during Gestation

The development of hematopoiesis begins early in embryonic life in the yolk sac, followed by the liver, bone marrow, and other secondary hematopoietic organs. Lymphopoiesis begins after erythropoiesis and myelopoiesis. The blue arrows illustrate hematopoietic cells and their progenitors (and precursors) migrating between hematopoietic organs at different stages of embryonic and fetal life. The diagram also represents the aorta–gonad–mesonephric (AGM) region which is an important structure supporting the early colonization of hema-topoietic organs by hematopoietic cells and their progenitors. Infants born very prematurely, between 22 (defining the absolute gestational limit of viability in humans) and 32 weeks, are at high risk of infection. This period also corresponds to a critical period where substantial maturation of antimicrobial PRRs occurs, beginning with endosomal/cytoplasmic, followed by extracellular PRRs. This period also likely overlaps with the beginning of the development of mature, adult-like fetal T cells from an earlier wave of fetal T cells. Concomitant to this is the passive immunization of fetuses through trans-placental maternal antibody transfer. All these events contribute to the immaturity of the neonatal immune system in the context of a preterm birth.

Figure 2. Metabolic Adaptation Occurring during Immune Activation

Resting immune cells, such as monocytes or T cells primarily produce energy (ATP) from breaking down glucose into pyruvate, and through mitochondrial oxidative phosphorylation. The activation of pattern recognition receptors (PRRs) by microbes leads to the activation of the master transcription regulator NF-κB, which in turn results in inflammatory cytokine gene expression and production (e.g. IL-1β, TNF-α). Concurrently, cells also undergo a metabolic shift to aerobic glycolysis (a phenomenon also known as the Warburg effect), where energy production occurring through glycolysis breaks down glucose into succinate. Although less energy is produced for each glucose molecule, this pathway does provide large quantities of anabolic substrates necessary to feed into the high gene transcriptional activity occurring during immune activation. Succinate and NF-κB also stabilize the transcription factor HIF-1α, resulting in further upregulation of inflammatory cytokine gene expression. The shift away from oxidative phosphorylation also allows these cells to produce reactive oxygen species (ROS) more efficiently. By contrast, anti-inflammatory signaling (via STAT6) causes an increase in fatty acid uptake, mitochondrial biogenesis, and increased mitochondrial function. This metabolic shift towards fatty acid oxidation leads to upregulation of anti-inflammatory cytokines (e.g., IL-10, TGF-β) and pro-resolving lipid mediators such as resolvins and protectins.