Globally, preterm birth is the leading cause of death for newborns and children under 5 years of age, yet little is known about the cause of this condition.
Some preterm births have been linked to a bacterium known as group B streptococcus (GBS), which is carried by about 25 percent of women in their vagina and rectum. Women who carry GBS are usually asymptomatic, but when they are pregnant, many deliver prematurely. However, in these cases, evidence of GBS infection has not been discovered in the feto-maternal barrier (the boundary between the fetus and the mother) or the womb itself.
The authors of a new PLOS Pathogens study hypothesized that, if GBS can send harmful bacterial products up the reproductive tract in tiny sacs called membrane-bound vesicles (MVs), this could lead to inflammation of the feto-maternal barrier, similar to the effects of live bacteria.
“Most cases of preterm deliveries are associated with inflammation in the womb. However, a puzzle remained regarding how inflammation could occur even in absence of any infection,” says Dr. Anirban Banerjee, the lead author of the study.
Using mouse models, Banerjee and colleagues verified their hypothesis that MVs can travel up the reproductive tract. They also discovered that GBS MVs lead to tissue damage, inflammation, and a condition known as chorio-amnionitis, which substantially weakens the feto-maternal barrier and the fetal membrane itself, all without the direct presence of bacteria.
“The most surprising breakthrough was finding the membrane vesicles to be specifically loaded with bacterial toxins and proteases which could degrade the collagen present in the feto-maternal barrier,” says Banerjee.
Finally, the scientists investigated the role of MVs in premature delivery. After MVs were injected directly into the amniotic sac of mice at later stages of pregnancy, about 60 percent of the fetuses were delivered prematurely, compared with just 10 percent of fetuses delivered by mice without MV injections. Similarly to live GBS bacteria, MVs also damaged the mouse fetuses themselves, with nearly 30 to 40 percent experiencing intrauterine fetal death (IUFD) and some stillborn.
Though the study is limited by its use of mouse models to explore a potential cause of preterm birth in humans, the results advance the field substantially.
“Our findings now reveal the fact that GBS produces MVs and thus efficiently delivers bacterial products up the reproductive tract,” says Banerjee. “This could now explain the reason for this unexplained inflammation at the feto-maternal barrier and subsequent premature birth.”
Banerjee says the next step is to determine whether MVs also have a direct effect on the fetus, as the results of this study indicate elevated rates of IUFD and stillbirths in mice injected with GBS MVs.
Surve MV, Anil A, Kamath KG, Bhutda S, Sthanam LK, Pradhan A, et al. (2016) Membrane Vesicles of Group B Streptococcus Disrupt Feto-Maternal Barrier Leading to Preterm Birth. PLoS Pathog 12(9): e1005816. doi: 10.1371/journal.ppat.1005816
Liu L, Johnson HL, Cousens S, Perin J, Scott S, et al. (2012) Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 379: 2151–2161. doi: 10.1016/S0140-6736(12)60560-1 PMID: 22579125
Image Credit: A premature baby born in Yekatit 12 hospital, Addis Ababa, Ethiopia ©UNICEF Ethiopia/2011/Pudlowski via Flickr