Compartmentalized Innate Immune Response of Human Fetal Membranes against Escherichia coli Choriodecidual Infection

Abstract

An infectious process into the uterine cavity represents a major endangered condition that compromises the immune privilege of the maternal–fetal unit and increases the risk for preterm birth (PTB) and premature rupture of membranes (PROM). Fetal membranes are active secretors of antimicrobial peptides (AMP), which limit bacterial growth, such as Escherichia coli. Nevertheless, the antibacterial responses displayed by chorioamniotic membranes against a choriodecidual E. coli infection have been briefly studied. The objective of this research was to characterize the profile of synthesis, activity, and spatial distribution of a broad panel of AMPs produced by fetal membranes in response to E. coli choriodecidual infection. Term human chorioamniotic membranes were mounted in a two independent compartment model in which the choriodecidual region was infected with live E. coli (1 × 105 CFU/mL). Amnion and choriodecidual AMP tissue levels and TNF-α and IL-1β secretion were measured by the enzyme-linked immunosorbent assay. The passage of bacterium through fetal membranes and their effect on structural continuity was followed for 24 h. Our results showed that E. coli infection caused a progressive mechanical disruption of the chorioamniotic membranes and an activated inflammatory environment. After the challenge, the amnion quickly (2–4 h) induced production of human beta defensins (HBD)-1, HBD-2, and LL-37. Afterwards (8–24 h), the amnion significantly produced HBD-1, HBD-2, HNP-1-3, S100A7, sPLA2, and elafin, whereas the choriodecidua induced LL-37 synthesis. Therefore, we noticed a temporal- and tissue-specific pattern regulation of the synthesis of AMPs by infected fetal membranes. However, fetal membranes were not able to contain the collagen degradation or the bacterial growth and migration despite the battery of produced AMPs, which deeply increases the risk for PTB and PROM. The mixture of recombinant HBDs at low concentrations resulted in increased bactericidal activity compared to each HBD alone in vitro, encouraging further research to study AMP combinations that may offer synergy to control drug-resistant infections in the perinatal period.

High Glucose Promotes Inflammation and Weakens Placental Defenses against E. coli and S. agalactiae Infection: Protective Role of Insulin and Metformin

“…Indeed, immune defense against infection involves complex mechanisms and, undoubtedly, a critical one is the synthesis of antimicrobial peptides [ 76 ]. Among them, HBDs are the most studied group of microbicidal peptides in the maternal–fetal interface [ 77 , 78 , 79 , 80 ]. In vitro and in vivo experiments have demonstrated that a high glucose concentration in sera or culture media diminished the production of HBDs [ 81 , 82 , 83 , 84 ].…”

Antimicrobial Peptides in Early-Life Host Defense, Perinatal Infections, and Necrotizing Enterocolitis—An Update

“…The highest expression has been observed for HBD-3, which is a dominant defensin in the amniotic epithelium. In vitro studies on cultured fetal membranes showed increased production of HNP-1 to -3 and HBD-1 and -2 in the presence of E. coli infection [ 123 ].…”

“…Cathelicidin LL-37 levels remain relatively unchanged throughout uncomplicated pregnancies ( Figure 3 ) [ 124 , 125 ]. Some researchers failed to demonstrate the presence of either HBD 2 or LL-37 in the AF of uncomplicated pregnancies, probably because the expression of these AMPs is inducible [ 106 , 123 ].…”

“…Levels in cervical mucus increase significantly during pregnancy and remain elevated after delivery [ 128 ]. Production of elafin and/or SLPI increases in response to microbial products (LPS), cytokines (IL-1, TNF-α), and α-defensins [ 69 , 76 , 116 , 123 , 129 ].…”

“… Schematic illustration of published data regarding changes in AMP expression and levels associated with chorioamnionitis, neonatal infections, and necrotizing enterocolitis (NEC). Abbreviations: ELBWI, extremely-low-birth-weight infants; LOS, late onset sepsis; PCs, Paneth cells [ 81 , 101 , 111 , 112 , 118 , 119 , 120 , 121 , 122 , 123 , 125 , 132 , 133 , 134 , 136 , 139 , 147 , 154 , 156 , 165 , 172 , 184 , 185 , 186 , 191 , 192 , 193 , 196 , 203 ]. …”