Membrane Vesicles of Group B Streptococcus Disrupt Feto-Maternal Barrier Leading to Preterm Birth

Abstract

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.

Perinatal Group B Streptococcal Infections: Virulence Factors, Immunity, and Prevention Strategies

“…Recent studies have described a role for extracellular membrane vesicles (MVs) in weakening of placental membranes [84]. GBS MVs contained multiple virulence factors, including: 1) HylB, 2) CAMP factor (Christine, Atkins, Munch-Peterson factor [85]), a secreted pore-forming protein [86] that may amplify [87], but is not essential for GBS virulence [88], 3) IgA binding protein, with the ability to bind human IgA [89] for host immune evasion [90] and 4) multiple enzymes that may regulate ECM degradation [84].…”

“…GBS MVs contained multiple virulence factors, including: 1) HylB, 2) CAMP factor (Christine, Atkins, Munch-Peterson factor [85]), a secreted pore-forming protein [86] that may amplify [87], but is not essential for GBS virulence [88], 3) IgA binding protein, with the ability to bind human IgA [89] for host immune evasion [90] and 4) multiple enzymes that may regulate ECM degradation [84]. Intra-amniotic administration of GBS MVs in pregnant mice caused significant damage to choriodecidual tissues and stimulated leukocytic infiltration and inflammation, leading to membrane weakening [84]. The specific role played by each virulence factors in the context of MVs remains unknown.…”

Group B streptococcus and respiratory syncytial virus immunisation during pregnancy: a landscape analysis

“…GBS also may contribute to birth asphyxia, prematurity and stillbirths; a recent systematic review estimated that GBS might account for up to 12% of stillbirths 21 . In vitro and animal data demonstrate that components of GBS are capable of disrupting critical maternal-fetal barriers during pregnancy resulting in tissue damage and inflammatory changes and thereby the potential to precipitate preterm labour [22][23][24][25] . However, it is more difficult to clearly establish this relationship in humans and the evidence currently is mixed 26 .…”

“…Robust data could then potentially be used to facilitate the licensure of a GBS vaccine without the need for large-scale pre-licensure efficacy trials in pregnant women 137 ; the approach taken for licensure of meningococcal C [23] and meningococcal B vaccines.…”

Protein Kinase C – Zeta Inhibitors: A New Hope for Controlling Maternal Intrauterine Infection Induced Premature Birth.

“…It also caused the apoptosis in chorio-decidual tissue. Thus, GBS membrane vesicles can cause chorio-amniontis, which increases the chances of premature birth [21]. Zahl and Bjerknes injected intra peritoneal the endotoxins of gram negative bacteria into 12-18 days pregnant mice, which resulted in abortion of the embryo [22].…”