Preterm birth—the birth of an infant before 37 weeks of pregnancy—is the greatest contributor to infant death, and a leading cause of long-term neurological disabilities in children. One of the causes of preterm birth is Group B Streptocuccus (GBS) infection in pregnant women. GBS frequently colonizes the lower genital tract of healthy women without causing any symptoms. However, it may cause severe infections during pregnancy by ascending from the lower genital tract into the amniotic cavity. Infection of the amniotic fluid can lead to fetal injury.
GSB is able to penetrate the human placenta with the help of a hemolytic pigment toxin, which consists of lipids. This toxin is a lipid that stains the bacteria orange/red and is able to induce not only hemolysis, or destruction of red blood cells, but also pyroptosis—a specific form of cell death—in macrophages, white blood cells that eliminate microscopic particles, such as bacteria and dead cells.
Now, results from a new study (Group B Streptococcus circumvents neutrophils and neutrophil extracellular traps during amniotic cavity invasion and preterm labor) published in the journal Science Immunology (October 14, 2016) show that the GBS pigment toxin damages neutrophils and neutrophil extracellular traps in placental membranes. The study was carried out using a pregnant nonhuman primate model that closely mimics pregnancy in humans and allows monitoring of uterine contractions, timing of microbial invasion of the amniotic cavity, and immune responses during pregnancy-associated infections. Using this model, researchers could follow the course of GBS infection from the initial stages until preterm labor, a process that would be impossible to experimentally follow in humans.
The researchers found that increased production of the hemolytic pigment toxin enables GBS to penetrate the placental membranes and infect amniotic fluid and fetal organs as early as within 15 minutes to within a few hours after infection. The infectious process induced increased release of messenger proteins that specifically recruit neutrophils. However, despite the recruitment of neutrophils, GBS producing large amounts of the hemolytic pigment toxin were able to infect multiple fetal organs.
Neutrophils are white blood cells involved as a first line of defense in controlling the spread of infectious microbes, and kill these microbes using a process called phagocytosis—they engulf and then digest the microbes using an arsenal of powerful toxic substances. Therefore the neutrophil is one type of phagocytic cell, so-called after the Greek for “devouring cells”. Neutrophils use an additional strategy to entangle, immobilize and kill microbes—they extrude stringy DNA webs known as neutrophil extracellular traps. Large numbers of neutrophils reside in the bone marrow and circulate in the blood. At the beginning of an infection, the early inflammatory process results in the production of a specialized set of cytokines and chemokines, protein messenger that signal neutrophils to travel from the blood and bone marrow to the site of infection.
The researchers found that the hemolytic pigment toxin induced neutrophil cell death. Therefore, when the neutrophils reached the site of infection to kill GBS following cytokine and chemokine signals, they were killed themselves by the GBS hemolytic pigment toxin, which damaged the neutrophils’ cell membrane. Moreover, the toxin induced formation of neutrophil extracellular traps in the placental membranes. However, GBS that produced large amounts of the hemolytic pigment toxin could not be killed by the neutrophil extracellular traps, and were therefore able to invade the amniotic fluid.
Together, the study results show that the hemolytic pigment toxin enables GBS to avoid killing by neutrophils and their extracellular traps. In absence of killing by neutrophils, GBS is able to damage the placental membranes and induce both fetal injury and preterm labor. The study results also indicate that the GBS hemolytic pigment toxin could be a target for novel strategies developed to prevent GBS infection in pregnant women and subsequent damage to the fetus.