Researchers show how a toxin made by GBS causes fetal injury and how that same toxin stimulates host immune cells to fight the bacteria.
In 2015, scientists at Seattle Children’s published two groundbreaking studies that describe the mechanism group B Streptococcus (GBS) uses to cause fetal injury in utero and how the host defends against these deadly bacteria.
The first study showed that a toxin produced by GBS pokes the membranes of host cells, leading to cell death.
“Many scientists and clinicians with a wide range of expertise – from biophysics, molecular biology and cell biology to immunology and gynecology – helped us figure out that GBS uses a lipid toxin as an arsenal to infiltrate host cells, including those in the host’s placenta,” says Dr. Lakshmi Rajagopal, lead author of the study.
The second study sheds light on an unexplained process: how pregnant mothers can defend against GBS infections. Using mouse models, the team showed that immune cells, called mast cells, are actually activated by the toxin.
“Mast cells don’t typically fight bacteria, they are mostly involved in human responses to allergens,” explains Rajagopal. “Our study shows that they do react to GBS by releasing front-line compounds that can recruit other host defenses to kill the bacteria. Mast cells appear to be an early defense system in a host’s effort to eradicate GBS, but much more study is needed.”
Unraveling the mystery
GBS is a type of bacteria commonly found in healthy women (men are not carriers). It typically does not cause infections in women, but it is the most common cause of bacterial infections for babies in utero, leading to fetal injury and preterm birth or stillbirth. In the U.S., pregnant women who test positive for GBS are given IV antibiotics during labor to prevent the newborn from being infected during birth. Still, there is no effective therapy to prevent infections to neonates in the womb.
Rajagopal’s research, funded by the National Institutes of Health, answers a long-studied question on how GBS causes infections in utero. “Understanding how an opportunistic pathogen like GBS works – and knowing the mechanisms a host uses to fight the bacteria – are key to developing a therapy that will stop GBS in its tracks,” says Rajagopal.
Eyes on the prize
Rajagopal’s previous GBS research, published in the Journal of Experimental Medicine in 2013, determined the hemolytic toxin found in GBS was not a protein, as previously believed, but a different cell structure known as a lipid. The finding may prevent the development of a vaccine for GBS, because the molecular structure of lipids prevents the toxin from being inactivated by antibodies – the traditional way that vaccines neutralize toxins made of protein molecules.
Now, with an understanding of the toxin’s structure as a lipid and a better grasp of how the toxin helps GBS cause fetal injury, Rajagopal and her colleagues will turn their attention to why some women carry GBS and others don’t.
“At any given time, about 30% of women are colonized with GBS, yet they don’t have it all the time,” says Rajagopal. “The bacteria will disappear and then come back, so there are lots of questions about why it colonizes women intermittently. At this point, we don’t have any idea.”
As Rajagopal and her team continue to unravel the mystery of GBS, they keep their eyes on the prize: mitigating GBS-induced fetal injury. “Our ultimate goal is to identify potential interventions or develop novel compounds that will stop the toxin from functioning and prevent infections in utero that lead to preterm births and stillbirths.”
GBS is the most common cause of life-threatening bacterial infections for babies in utero.