Group B streptococcal phospholipid causes pulmonary hypertension

Abstract

Group B Streptococcus is the most common cause of bacterial infection in the newborn. Infection in many cases causes persistent pulmonary hypertension, which impairs gas exchange in the lung. We purified the bacterial components causing pulmonary hypertension and identified them as cardiolipin and phosphatidylglycerol. Synthetic cardiolipin or phosphatidylglycerol also induced pulmonary hypertension in lambs. The recognition that bacterial phospholipids may cause pulmonary hypertension in newborns with Group B streptococcal infection opens new avenues for therapeutic intervention.G roup B Streptococcus (GBS) is the most frequent cause of sepsis and meningitis in the human newborn (1). Despite prompt treatment with antibiotics, neonates with GBS infection are often quite ill and the fatality rate is 5% (2). Respiratory distress, a prominent sign in these babies, is caused by pulmonary hypertension induced by the GBS infection (3). The pulmonary hypertension reflects an increase in pulmonary vascular resistance, which impairs exchange of oxygen and carbon dioxide. Infusion of live or heat-killed GBS into sheep promptly induces pulmonary hypertension, with little or no effect on systemic pressure (4). This response has been reproduced by many investigators, who also established that the pulmonary hypertension is not a consequence of simple embolization because infusion of latex beads of the same size as GBS caused no change in pulmonary physiology (5). The hypertension is mediated by an increase in thromboxane A 2 , so that treatment with cyclooxygenase inhibitors such as indomethacin or with thromboxane synthesis inhibitors prevents or reverses the increase in pulmonary pressure (5, 6). However, the component(s) of GBS that activate thromboxane synthesis are unknown. Guided by bioassays performed in neonatal lambs (7), we undertook the purification and identification of these components, using standard biochemical techniques. Materials and Methods Purification and Analysis of Pulmonary Hypertensive Compounds fromGBS. Biochemical fractionation procedures were linked in series to develop an initial purification protocol, which was modified to give the final protocol described here. At each step, fractions were assayed for pulmonary arterial hypertensive activity in 3-to 12-day-old lambs of Ϸ5 kg, as described (7). We previously demonstrated that pulmonary arterial pressure measurements were a valid surrogate for measurement of pulmonary vascular resistance in this animal model (7). Fractions were infused peripherally into the femoral vein, not directly into the pulmonary artery. Fractions were considered active if they increased pulmonary arterial pressure by at least 50% in at least two lambs tested on different days.GBS type III, strain 878 was grown to mid-or late-log phase (7), washed with sterile normal saline, heat-killed by incubation in a 60°C water bath for 90 min, pelleted by centrifugation, and resuspended in saline to an OD of 2.0 at 650 nm. Heat-killed GBS (3-gm wet weight) were extracted with 40 ml of ...

Group B <i>Streptococcus</i> Exposure and Self-Limited Respiratory Distress in Late Preterm and Term Neonates

“…During this same time period, a total of 16,832 women with known GBS status delivered a late preterm or term baby at our institution. Consistent with the overall epidemiology of GBS colonization in the third trimester in the USA [13] 3,872 or 23.0% were colonized with GBS. The crude incidence of self-limited respiratory distress among infants born to GBS-positive mothers at ≥37 weeks of GA was 11 ± 3 cases per 1,000 term births, which was statistically identical to the crude incidence of 12 ± 2 cases per 1,000 cases of self-limited respiratory distress among GBS-negative mothers.…”

“…In mammalian models, lysis of GBS by antibiotics liberates bacterial cell wall components, which activate the host inflammatory cascade and result in mild pulmonary hypertension [13,14,15]. Symptoms of this mild pulmonary hypertension in lambs include self-resolving tachypnea and mild hypoxemia, and are clinically identical to symptoms of human self-limited respiratory distress.…”

Maternal Colonization with Group B <b><i>Streptococcus</i></b> Is Associated with an Increased Rate of Infants Transferred to the Neonatal Intensive Care Unit

“…Another biologically plausible explanation for our findings is pulmonary hypertension induced by phospholipids released by GBS (alive or dead). This mechanism has been demonstrated in lambs [18] , although Stroustrup et al [22] did not confirm a link between intrapartum exposure to GBS and self-limiting respiratory distress.…”

Streptococcus pneumoniae,S. pyogenes, andS. agalactiaemembrane phospholipid remodeling in response to human serum

“…In contrast, little is known about the cellular membrane composition and dynamics of streptococci. Earlier studies mainly utilized thin layer chromatography (TLC) or column separation coupled with paper chromatography to study membrane lipids extracted from cultures in routine laboratory medium (14)(15)(16)(17)(18)(19). However, these methods lack molecular specificity and sensitivity for the comprehensive characterization of membrane lipids (20).…”