ABSTRACT
BACKGROUND: Bacterial sepsis is a major threat in neonates born prematurely, and is associated with elevated morbidity and mortality. Little is known on the innate immune response to bacteria among extremely premature infants. METHODOLOGY/PRINCIPAL FINDINGS: We compared innate immune functions to bacteria commonly causing sepsis in 21 infants of less than 28 wks of gestational age, 24 infants born between 28 and 32 wks of gestational age, 25 term newborns and 20 healthy adults. Levels of surface expression of innate immune receptors (CD14, TLR2, TLR4, and MD-2) for Gram-positive and Gram-negative bacteria were measured in cord blood leukocytes at the time of birth. The cytokine response to bacteria of those leukocytes as well as plasma-dependent opsonophagocytosis of bacteria by target leukocytes was also measured in the presence or absence of interferon-γ. Leukocytes from extremely premature infants expressed very low levels of receptors important for bacterial recognition. Leukocyte inflammatory responses to bacteria and opsonophagocytic activity of plasma from premature infants were also severely impaired compared to term newborns or adults. These innate immune defects could be corrected when blood from premature infants was incubated ex vivo 12 hrs with interferon-γ. CONCLUSION/SIGNIFICANCE: Premature infants display markedly impaired innate immune functions, which likely account for their propensity to develop bacterial sepsis during the neonatal period. The fetal innate immune response progressively matures in the last three months in utero. Ex vivo treatment of leukocytes from premature neonates with interferon-γ reversed their innate immune responses deficiency to bacteria. These data represent a promising proof-of-concept to treat premature newborns at the time of delivery with pharmacological agents aimed at maturing innate immune responses in order to prevent neonatal sepsis.
Subject(s)
Immunity, Innate/immunology , Infant, Extremely Low Birth Weight/immunology , Infant, Premature/immunology , Interferon-gamma/therapeutic use , Sepsis/drug therapy , Sepsis/immunology , Body Weight , Cell Line , Female , Fetal Blood/cytology , Fetal Blood/immunology , Flow Cytometry , Gestational Age , Humans , Infant, Newborn , Leukocytes/metabolism , Male , Phagocytosis/physiology , Pregnancy , Receptors, Immunologic/metabolism , Statistics, NonparametricABSTRACT
Bacillus cereus is an aerobic or facultative anaerobic Gram-positive rod which is ubiquitous in the environment. The incidence of neonatal infections is very low. The clinical course is serious, usually life- threatening or permanently damaging the central nervous system. The immature immune system, subjected to invasive procedures, increases the morbidity risk in this age group, especially in extremely low birth weight infants. Diagnostic difficulties and insusceptibility to ''first- line'' antibiotics can delay effective therapy and increase the risk of its failure. We report a 730 g preterm neonate, delivered at 27 weeks gestation with late- onset sepsis due to Bacillus cereus. The disease course was complicated by development of brain abscesses. We describe the clinical course of infection, diagnostic difficulties and the treatment. After the 140 days of hospitalization and relatively long period of therapy with different antibiotics, the patient was discharged from hospital in good condition. Despite of transmission of infection to the central nervous system, the introduced therapy prevented severe neurological disabilities as confirmed during the evaluation according to the Bayley Scale of Infant Development, performed at 29 months of life.
Subject(s)
Bacillus cereus/isolation & purification , Brain Abscess/microbiology , Infant, Extremely Low Birth Weight , Infant, Premature, Diseases/diagnosis , Infant, Premature, Diseases/microbiology , Sepsis/diagnosis , Sepsis/microbiology , Anti-Bacterial Agents/therapeutic use , Brain Abscess/diagnosis , Brain Abscess/drug therapy , Female , Humans , Infant, Newborn , Infant, Premature, Diseases/drug therapy , Sepsis/drug therapyABSTRACT
Myeloid differentiation factor 2 (MD-2) binds Gram-negative bacterial lipopolysaccharide with high affinity and is essential for Toll-like receptor 4-dependent signal transduction. MD-2 has recently been recognized as a type II acute phase protein. Plasma concentrations of the soluble form of MD-2 increase markedly during the course of severe infections. Its production is regulated in hepatocytes and myeloid cells by interleukin-6 (IL-6) but not IL-1beta. In the present work we show that two transcription factors (TF), PU.1 and CAAT/enhancer-binding protein beta (C/EBPbeta), participate in the activation of the human MD-2 gene in hepatocytic cells after stimulation with IL-6. PU.1 TF and proximal PU.1 binding sites in the MD-2 promoter were shown to be critical for the basal activity of the promoter as well as for IL-6-induced soluble MD-2 production. Deletions of proximal portions of the MD-2 promoter containing PU.1 and/or NF-IL-6 consensus binding sites as well as site-directed mutagenesis of these binding sites abrogated IL-6-dependent MD-2 gene activation. We show that the cooperation between C/EBPbeta and PU.1 is critical for the transcriptional activation of the MD-2 gene by IL-6. PU.1 was essentially known as a TF involved in the differentiation of myeloid precursor cells and the expression of surface receptors of the innate immunity. Herein, we show that it also participates in the regulation of an acute phase protein, MD-2, in nonmyeloid cells cooperatively with C/EBPbeta, a classical IL-6-inducible TF.