Potential of immunomodulatory agents for prevention and treatment of neonatal sepsis

Abstract

Prevention of neonatal infection-related mortality represents a significant global challenge particularly in the vulnerable premature population. The increased risk of death from sepsis is likely due to the specific immune deficits found in the neonate as compared to the adult. Stimulation of the neonatal immune system to prevent and/or treat infection has been attempted in the past largely without success. In this review, we identify some of the known deficits in the neonatal immune system and their clinical impact, summarize previous attempts at immunomodulation and the outcomes of these interventions, and discuss the potential of novel immunomodulatory therapies to improve neonatal sepsis outcome.

Figure 1. Interaction of Microbiota and Neonatal Intestine

The interaction between intestinal bacteria and intestinal epithelium is necessary for homeostasis and normal function of repair mechanisms. Disruption of this interaction, through the use of antibiotics or via stress to the organism (i.e. remote infection or hypoxia), results in loss of homeostasis and degradation of the intestinal boundaries with subsequent microbial translocation.

Figure 2. Toll-Like Receptors (TLRs) and Their Respective Agonists

Schematic representation of toll-like receptors, both cell surface and endocytic, as well as their respective ligands. Stimulation of these receptors causes enhanced immune function through increased cellular cytokine production and improvement of antimicrobial effector mechanisms such as cellular phagocytosis and antimicrobial protein and peptide (APP) production. LTA-lipotechoic acid. PG-peptidoglycan. LPS-lipopolysaccharide.

Figure 3. Effect of TLR agonist Pretreatment on Sepsis Survival, Cytokine Production, Bacteremia, and Innate Cellular Function in Neonatal Mice

Systemic administration of select TLR agonists prior to the initiation of experimental polymicrobial sepsis significantly reduces murine neonatal mortality and is associated with a more robust but shortened inflammatory response and unique improvements in cell function (increased phagocytosis and reactive oxygen species production) with associated decreases in bacteremia as compared to saline pretreated neonatal mice.