Role of innate host defenses in susceptibility to early-onset neonatal sepsis

Abstract

Neonatal sepsis continues to take a devastating toll globally. Although adequate to protect against invasive infection in most newborns, the distinct function of neonatal innate host defense coupled with impairments in adaptive immune responses increases the likelihood of acquiring infection early in life, with subsequent rapid dissemination and death. Unique differences exist between neonates and older populations with respect to the capacity, quantity, and quality of innate host responses to pathogens. Recent characterization of the age-dependent maturation of neonatal innate immune function has identified novel translational approaches that may lead to improved diagnostic, prophylactic, and therapeutic modalities.

Figure 1. Role of innate immunity in responses to in utero infection

Early onset sepsis is typically caused by an ascending maternal lower genital tract infection. Antimicrobial proteins and peptides (APPs) within the vagina and amniotic fluid help to reduce bacterial burden and are up-regulated during infection. Pathogen detection begins with placental trophoblast cell Toll-like receptors (TLR) that up-regulate APP and inflammatory cytokine production. Neonatal monocytes are simultaneously stimulated via TLR-mediated pathogen detection with subsequent cytokine production that in turn activates innate immune function (neutrophils, macrophages) and induces the hepatic production of acute phase reactants. Innate immunity within the skin and vernix (APPs) facilitates appropriate commensal microbial colonization associated with erythema toxicum.

Figure 2. Comparison of neonatal and adult levels of opsonins and antimicrobial proteins and peptides

A. Complement functional assays and complement proteins, mannose-binding lectin, and IgG concentrations in preterm neonates, term neonates, and adults. (Reproduced with permission from Lewis DB and Wilson CB. “Developmental Immunology and Role of Host Defenses in Fetal and Neonatal Susceptibility to Infection. Pgs 87-210, In ”Infectious Diseases of the Fetus and Newborn Infant“: 2006 Elsevier Saunders, Philadelphia. Remington, Klein, Wilson, and Baker.) *- Reproduced with permission from Lau YL, et al. Mannose-binding protein in preterm infants: developmental profile and clinical significance. Clin Exp Immunol 102:649, 1995, **-Reproduced with permission from Fanaroff AA, et al. Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants. The National Institute of Child Health and Human Development Neonatal Research Network. Pediatr Infect Dis J 17:593, 1998. B. Serum antimicrobial protein and peptide levels in preterm neonates, term neonates, and maternal levels. (Reproduced with permission from Strunk T, et al. Reduced levels of antimicrobial proteins and peptides in human cord blood plasma. Arch Dis Child Fetal Neonatal Ed 94:F230, 2009.). MBL-mannose-binding lectin, BPI-bactericidal/permeability-increasing protein, sPLA2-Secretory phospholipase 2, HNP-human neutrophil peptide.