Abstract
BackgroundBacterial 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 FindingsWe 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/SignificancePremature 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.
Highlights
Twenty percent of premature infants surviving beyond the first three days of life will develop one or more culture-proven bacteraemic sepsis
We show that premature infants, and neonates with extremely low birth weight (ELBW), are born with an immature innate immunity resulting in a profound defect in the recognition and the clearance of bacteria
These defects in the capacity to mount a proper inflammatory response and to phagocytise bacteria are likely to account for the high incidence of neonatal sepsis associated with extreme prematurity
Summary
Twenty percent of premature infants surviving beyond the first three days of life will develop one or more culture-proven bacteraemic sepsis. As much as 46% of infants born before 25 weeks of gestational age will develop sepsis [1]. The prevalence of neonatal sepsis is inversely correlated with gestational age and birth weight, and is associated with morbid complications such as bronchopulmonary dysplasia, cerebral palsy, an increased hospital length of stay, and a high mortality rate [1,3]. Whereas sepsis secondary to coagulase-negative staphylococci, is rarely fatal, neonatal sepsis due to Gram-negative bacteria is associated with an elevated mortality [2]. Innate immune defences against bacteria rely on soluble proteins (mainly opsonins, complement and maternal immunoglobulins) and phagocytes such as neutrophils. 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
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