Group B streptococcus activates transcriptomic pathways related to premature birth in human extraplacental membranes in vitro†,‡

Abstract

Streptococcus agalactiae (group B streptococcus [GBS]) infection in pregnant women is the leading cause of infectious neonatal morbidity and mortality in the United States. Although inflammation during infection has been associated with preterm birth, the contribution of GBS to preterm birth is less certain. Moreover, the early mechanisms by which GBS interacts with the gestational tissue to affect adverse pregnancy outcomes are poorly understood. We hypothesized that short-term GBS inoculation activates pathways related to inflammation and premature birth in human extraplacental membranes. We tested this hypothesis using GBS-inoculated human extraplacental membranes in vitro. In agreement with our hypothesis, a microarray-based transcriptomics analysis of gene expression changes in GBS-inoculated membranes revealed that GBS activated pathways related to inflammation and preterm birth with significant gene expression changes occurring as early as 4 h postinoculation. In addition, pathways related to DNA replication and repair were downregulated with GBS treatment. Conclusions based on our transcriptomics data were further supported by responses of prostaglandin E2 (PGE2), and matrix metalloproteinases 1 (MMP1) and 3 (MMP3), all of which are known to be involved in parturition and premature rupture of membranes. These results support our initial hypothesis and provide new information on molecular targets of GBS infection in human extraplacental membranes.

Modulation of Death and Inflammatory Signaling in Decidual Stromal Cells following Exposure to Group B Streptococcus

“…We anticipate that GBS-mediated alteration of specific inflammatory and immune responses impacts the ability of infected mothers and neonates to appropriately recognize and respond to GBS infection. Changes in the regulation of cell survival, cytoskeleton rearrangements, and cell-cell contacts are likely to influence GBS colonization and invasion of host cells and negatively impact the integrity of infected tissue, which may also contribute to extraplacental membrane weakening as was discussed in a prior study (25). Additionally, GBS-mediated modulation of cellular metabolism, hormone signaling, and angiogenesis could have severe impacts on fetal development, perhaps contributing to outcomes such as miscarriage or stillbirth.…”

Streptococcuspyogenes infects human endometrium by limiting the innate immune response

“…The low induction level of GAS contrasts with much higher induction level by GBS in a similarly set-up of infection (33). GBS infection modified the expression of 32, out of these 133 genes, and, furthermore, the most activated genes compared to uninfected tissue are related to cellular response to cytokine stimulus (33). This supports the capacity of the decidua to elicit an immune response.…”

“…This expression pattern suggested that either ex vivo decidua is unable to mount an immune response or that GAS infection restrains this response. The low induction level of GAS contrasts with much higher induction level by GBS in a similarly set-up of infection (33). GBS infection modified the expression of 32, out of these 133 genes, and, furthermore, the most activated genes compared to uninfected tissue are related to cellular response to cytokine stimulus (33).…”

Toxicant Disruption of Immune Defenses: Potential Implications for Fetal Membranes and Pregnancy

“…A recent publication from our laboratory showed that GBS inoculation caused a release of molecular effectors of parturition (matrix metalloproteinases and prostaglandin E2) from human FM explant punches in vitro (Park et al, 2018). In addition, pathway analysis of transcriptomic responses showed that pathways related to inflammation and PTB were activated by GBS inoculation (Park et al, 2018). Studies from our laboratory showed that a metabolite of trichloroethylene (TCE), a common environmental contaminant, modifies innate immune response to GBS in FM explants (Boldenow et al, 2015).…”

“…In women, GBS infection is associated with PTB at less than 32 weeks gestation (Hillier et al, 1991) and with chorioamnionitis, an inflammation of the chorion layer of the FM (Anderson et al, 2007). A recent publication from our laboratory showed that GBS inoculation caused a release of molecular effectors of parturition (matrix metalloproteinases and prostaglandin E2) from human FM explant punches in vitro (Park et al, 2018). In addition, pathway analysis of transcriptomic responses showed that pathways related to inflammation and PTB were activated by GBS inoculation (Park et al, 2018).…”