Perinatal Gram-Positive Bacteria Exposure Elicits Distinct Cytokine Responses In Vitro.

Ludwig Deml,Maria Emilia Solano,Edith Reuschel,Sebastian Haeusler,Martina Toelge,Birgit Seelbach-Goebel

doi:10.3390/ijms22010332

Abstract

During pregnancy, infections caused by the gram-positive bacteria Enterococcus faecalis (E. faecalis), Streptococcus agalacticae (S. agalacticae), and Staphylococcus aureus (S. aureus) are major reasons for preterm labor, neonatal prematurity, meningitis, or sepsis. Here, we propose cytokine responses to bacterial infections by the immature perinatal immune system as central players in the pathogenesis of preterm birth and neonatal sepsis. We aimed to close the gap in knowledge about such cytokine responses by stimulating freshly isolated umbilical blood mononuclear cells (UBMC) with lysates of E. faecalis, S. agalacticae, and S. aureus collected from pregnant women in preterm labor. Bacterial lysates and, principally, S. aureus and S. agalacticae distinctly triggered most of the eleven inflammatory, anti-inflammatory, TH1/TH2 cytokines, and chemokines quantified in UBMC culture media. Chemokines depicted the most robust induction. Among them, MIP-1β was further enhanced in UBMC from female compered to male newborn infants. Due to its stability and high levels, we investigated the diagnostic value of IL-8. IL-8 was critically upregulated in cord blood of preterm neonates suffering from infections compared to gestational age-matched controls. Our results provide novel clues about perinatal immunity, underscoring a potential value of IL-8 for the timely detection of infections and suggesting that MIP-1β constitutes an early determinant of sex-specific immunity, which may contribute, e.g., to male’s vulnerability to preterm birth.

Highlights

Prematurity due to preterm birth is a main cause of short-term or long-term neonatal morbidities [1] and even death
Given that perinatal E. coli infection has already been the subject of thorough investigations [26], the aim of our present study was to characterize in depth the cytokine responses specific to the three clinically relevant vaginally occurring gram-positive bacteria frequently found in pregnant women with preterm labor, namely S. agalacticae, E. faecalis, and S. aureus
Establishedan an in in vitro in in which freshly isolated from healthy neonates born at term were incubated for h with the lysates from the selected neonates born at term were incubated for 36 h with the lysates from the selected gram- grampositive vaginally occurring found vaginal swabs of pregnant with positive vaginally occurring bacteria bacteria found in in vaginal swabs of pregnant women women with impending preterm birth:S

Summary

Introduction

Prematurity due to preterm birth is a main cause of short-term (e.g., respiratory distress and intraventricular hemorrhage) or long-term neonatal morbidities [1] and even death. It is typically considered that intrauterine infections induce the release of potent inflammatory mediators, such as cytokines and chemokines, which promote leukocyte recruitment and inflammation and result in premature uterine contractions and birth [5]. The gram-positive Enterococcus faecalis (E. faecalis), Group B Streptococcus (GBS), and Staphylococcus aureus (S. agalactiae) were highly prevalent, being respectively detected in 64%, 24%, and 10% of women with impeding preterm birth [8]. These three gram-positive bacteria species are often present in the vaginal microbiome [10], they can mediate opportunistic perinatal infections, chorioamnionitis, and/or neonatal sepsis, causing a substantial disease burden to Intensive

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