How GBS bacteria can cause preterm birth
Approximately 20-30% of healthy, adult women carry Group B Streptococcus (GBS) bacteria — vaginally or rectally. Though GBS can be harmless, it also causes premature birth and pregnancy complications in mice.
A study in PLOS Pathogens reports Group B Streptococcus (GBS) bacteria in mice produces small fluid filled sacs (vessicles) bound together into a membrane, bits of bacteria that can attack their host. In mice, these vesicles move from the vagina to the uterus inflamming membranes around fetal pups. Injected into the amniotic cavity, these vesicles can induce preterm and still births.
Membrane-bound Vesicles (MVs) loaded with toxins, immune-modifiers, and other bacterial factors, contribute to the survival and potential virulence (the ability to cause disease) in many pathogenic bacteria. However, whether GBS produces MVs was not known. In pregnant women who carry GBS and deliver prematurely, bacterial infection is rarely found in the womb.
Anirban Banarjee PhD, from the Department of Biosciences and Bioengineering, Indian Institute of Technology-Bombay, Mumbai, India, and his colleagues hypothesize that if GBS produces Membrane-bound Vesicles (MVs), these vessicles might move up to the womb during pregnancy and cause tissue damage where mother and fetus interface.
To test their theory, researchers grew GBS in liquid media, removed the bacteria, then used electron microscopy to examine the remaining liquid.
They found numerous spherical structures, vesicles just budding off each bacterial cell, confirming GBS produces Membrane-bound Vesicles (MVs).
They next examined the protein content of the MVs and identified 8 bacterial proteins, all virulent that can attack a human host and cause disease.
Researchers then mixed Membrane-bound vesicles (MVs) and human cells findng that MVs can also invade and kill human cells, suggesting GBS MVs are toxic to a human host.
Membrane-bound Vesicles (MVs) without bacteria were introduced into mouse vaginas and hours later were traced throughout the uterus and developing fetuses, indicating MVs can indeed travel up the birth canal. Adding MVs to mouse chorio-decidual membrane (located at the interface between mother and fetus) caused collagen to degrade, reduced that membrane's elasticity and weakened its mechanical properties.
When the researchers injected MVs directly into the amniotic sac (the fluid-filled cavity surrounding the embryo) of pregnant mice, they observed 24 hours later that tissue of the interface between mother and fetus was severely disrupted, with broken collagen fibers — hallmarks of inflammation, and signs of extensive cell death.
To determine whether such changes could lead to pre-term birth, researchers carefully monitored mice whose amniotic sacs had been injected with MVs at day 14.5 of pregnancy (a full-term mouse pregnancy lasts 19 days). Approximately 60% of the fetuses were born prematurely (by day 18) compared with a control group injected with saline where only 10% of pups were born prematurely.
Along with preterm birth, researchers also observed increased frequency of fetal death in utero. Pups born to MV injected mothers were small, some with abnormal morphology. Collectively, results suggest GBS MVs can cause preterm birth and fetal injury.
Researchers emphasize their results reveal MVs alone could induce features resembling clinical chorio-amnionitis in mice. "Clinically this observation is highly relevant as 50-80% women with chorio-amnionitis [also known as intra-amniotic infection (IAI)] do not have bacteria in their amniotic fluid or decidual tissue." They hypothesize that "MVs secreted by pathogens residing in the lower genital tract, may be responsible for cases of unexplained chorio-amnionitis."
Acknowledging the gap between experimental results in mice following direct injection of MVs into their amnion sac, and human pathogenesis, researchers nevertheless suggest their findings "provide a novel insight into how GBS — while simply sitting in the vagina — can orchestrate events at the fetal membrane leading to premature birth."
Because MVS are not susceptible to antibiotics, researchers speculate that "new drugs that prevent vesicle production may be a viable therapeutic option to prevent GBS mediated preterm birth."
Infection of the genitourinary tract with Group B Streptococcus (GBS), an opportunistic gram positive pathogen, is associated with premature rupture of amniotic membrane and preterm birth. In this work, we demonstrate that GBS produces membrane vesicles (MVs) in a serotype independent manner. These MVs are loaded with virulence factors including extracellular matrix degrading proteases and pore forming toxins. Mice chorio-decidual membranes challenged with MVs ex vivo resulted in extensive collagen degradation leading to loss of stiffness and mechanical weakening. MVs when instilled vaginally are capable of anterograde transport in mouse reproductive tract. Intra-amniotic injections of GBS MVs in mice led to upregulation of pro-inflammatory cytokines and inflammation mimicking features of chorio-amnionitis; it also led to apoptosis in the chorio-decidual tissue. Instillation of MVs in the amniotic sac also resulted in intrauterine fetal death and preterm delivery. Our findings suggest that GBS MVs can independently orchestrate events at the feto-maternal interface causing chorio-amnionitis and membrane damage leading to preterm birth or fetal death.
PLOS Pathogens: http://dx.plos.org/10.1371/journal.ppat.1005816
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Funding: MVS and SB acknowledge University Grants Commission (UGC, Govt. of India), AA acknowledges Council of Scientific and Industrial Research (CSIR, Govt. of India) and KGK acknowledges Department of Science and Technology (DST, Govt. of India) for fellowships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Citation: 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
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