Immaturity of Infection Control in Preterm and Term Newborns Is Associated with Impaired Toll‐Like Receptor Signaling

Abstract

The impaired infection control related to the functional immaturity of the neonatal immune system is an important cause of infection in preterm newborns. We previously reported that constitutive Toll-like receptor (TLR) 4 expression and cytokine secretion on lipopolysaccharide (LPS) stimulation increases with gestational age. Here, we analyzed constitutive monocyte TLR2 expression and evaluated the expression profiles of the proximal downstream adapter molecule myeloid differentiation factor 88 (MyD88). We further investigated activation of protein kinases p38 and extracellular regulated kinsase (ERK) 1/2 in CD14 monocytes after ex vivo stimulation with bacterial TLR ligands (LPS and lipoteichoic acid [LTA]). The functional outcome of the stimulation was determined by cytokine secretion. Monocytes from 31 preterm newborns (<30 weeks of gestation, n=16; 30-37 weeks of gestation, n=15), 10 term newborns, and 12 adults were investigated. In contrast to TLR4 expression, TLR2 levels did not differ between age groups. However, MyD88 levels were significantly lower in preterm newborns. Activation of p38 and ERK1/2 was impaired in all newborn age groups after stimulation with TLR-specific ligands. Accordingly, after LTA stimulation, the levels of interleukin (IL)-1 beta , IL-6, and IL-8 cytokine production were substantially lower (P<.001) in preterm newborns than in adults. The reduced functional response to bacterial cell wall components appears to be part of the functional immaturity of the neonatal immune system and might predispose premature newborns to bacterial infection.

Human β-defensin 2 expression in ELBW infants with severe necrotizing enterocolitis

“…It is also in line with the low expression profile for TLR4 described in monocytes of ELBW infants as compared with term infants (22). In contrast, conflicting data come from recent observations made in a mouse model where NEC is induced by formula feeding, hypoxia, and LPS exposure.…”

“…Mortality rate of severe NEC was 66% (n = 4) with no further deaths in the remaining patients. A total of 732 fecal samples were available (mean 11 per individual, range [5][6][7][8][9][10][11][12][13][14].…”

“…The authors concluded that the inability to sense LPS rather than an over-reaction to it might predispose ELBW infants to NEC (13). In addition, TLR4 levels were found to be significantly lower in monocytes of ELBW infants as compared with healthy term infants, leading to an impaired cytokine production on LPS stimulation (14). Currently, it is therefore unclear whether overstimulation, immaturity, or dysregulation of the immune system is responsible for an increased risk of NEC in premature ELBW infants.…”

Phagocytosis of neonatal pathogens by peripheral blood neutrophils and monocytes from newborn preterm and term infants

“…Cord blood is routinely used as a noninvasive, easily accessible neonatal sample as a surrogate for peripheral samples in immunological studies (24,26,27). However, the correlation between phagocytosis in cord and peripheral blood has not been reported previously.…”

Attenuated innate immune defenses in very premature neonates during the neonatal period

“…Toll-like receptors (TLRs) play a predominant role as a major family of PRR that act as essential "detectors" in the recognition of microbial pathogens by the innate immune system. We and others have shown that TLR-induced cytokine immune reactivity are profoundly attenuated in cord blood of very preterm neonates and develops asynchronously over the last trimester of gestation (6)(7)(8)(9)(10). These infants also display sustainably high levels of systemic inflammation, indicating a potential immune dysregulation that has also been associated with worsened clinical outcomes (11).…”