bims-reprim Biomed News
on Reproductive immunology
Issue of 2020‒12‒06
three papers selected by
Iva Filipovic
Karolinska Institutet

  1. Am J Obstet Gynecol. 2020 Nov 25. pii: S0002-9378(20)31331-4. [Epub ahead of print]
      BACKGROUND: Group B Streptococcus (GBS) is a common vaginal bacterium and leading cause of invasive fetoplacental infections. GBS in the vagina can invade through the cervix to cause ascending uteroplacental infections or can be transmitted to the neonate during vaginal delivery. Some studies have found that women with a "dysbiotic" polymicrobial and/or Lactobacillus-depleted vaginal microbiota are more likely to harbor GBS. Gardnerella vaginalis is often the most abundant bacteria in the vaginas of women with dysbiosis, while being detected at lower levels in most other women, and has been linked with several adverse pregnancy outcomes. Mouse models of GBS and G. vaginalis colonization have been reported but the two have not, to our knowledge, been studied together. The overarching idea driving this study is that certain members of the dysbiotic vaginal microbiota, such as G. vaginalis, may directly contribute to the increased rate of GBS vaginal colonization observed in women with vaginal dysbiosis.OBJECTIVE: We used a mouse model to test the hypothesis that vaginal exposure to G. vaginalis may facilitate colonization and/or invasive infection of the upper reproductive tract by GBS during pregnancy.
    STUDY DESIGN: Timed-pregnant mice were generated using an allogeneic mating strategy with BALBc males and C57Bl/6 females. Dams were vaginally inoculated at gestational day (E)14 with GBS-alone (using a 10-fold lower dose than previously reported models) or co-inoculated with GBS and G. vaginalis. Bacterial titers were enumerated in vaginal, uterine horn and placental tissues at E17. The presence (Fisher's exact tests) and levels (Mann-Whitney tests) of bacterial titers were compared between mono- and co-inoculated dams in each compartment. Relative risks were calculated for outcomes that occurred in both groups. Tissue samples were also examined for evidence of pathophysiology.
    RESULTS: Inoculation of pregnant mice with 107 GBS alone did not result in vaginal colonization or ascending infection. In contrast, co-inoculation of GBS with G. vaginalis in pregnant mice resulted in a 10-fold higher risk of GBS vaginal colonization (RR:10.31, 95%CI: 2.710-59.04; P=0.0006, Fishers Exact). Ascending GBS infection of the uterus and placenta occurred in approximately 40% of co-inoculated animals, whereas none of those receiving GBS alone developed uterine or placental infections. Immunofluorescence microscopy revealed GBS in both the maternal and fetal side of the placenta. Histological inflammation and increased pro-inflammatory cytokines were evident in the setting of GBS placental infection. Interestingly, placentas from dams exposed to GBS and G. vaginalis, but without recoverable vaginal or placental bacteria, displayed distinct histopathologic features and cytokine signatures.
    CONCLUSION: These data suggest that G. vaginalis vaginal exposure can promote GBS vaginal colonization, resulting in greater likelihood of invasive perinatal GBS infections. These findings suggest that future clinical studies should examine whether the presence of G. vaginalis is a risk factor for GBS vaginal colonization in women. Since G. vaginalis can also be present in women without BV, these findings may be relevant both inside and outside of the context of vaginal dysbiosis.
    Keywords:  Gardnerella vaginalis, Group B Streptococcus; ascending infection; bacterial vaginosis; health disparities; microbiota; placenta; uterus; vagina; vaginal microbiome
  2. Front Physiol. 2020 ;11 592689
      Placental insufficiency is implicated in spontaneous preterm birth (SPTB) associated with intrauterine inflammation. We hypothesized that intrauterine inflammation leads to deficits in the capacity of the placenta to maintain bioenergetic and metabolic stability during pregnancy ultimately resulting in SPTB. Using a mouse model of intrauterine inflammation that leads to preterm delivery, we performed RNA-seq and metabolomics studies to assess how intrauterine inflammation alters gene expression and/or modulates metabolite production and abundance in the placenta. 1871 differentially expressed genes were identified in LPS-exposed placenta. Among them, 1,149 and 722 transcripts were increased and decreased, respectively. Ingenuity pathway analysis showed alterations in genes and canonical pathways critical for regulating oxidative stress, mitochondrial function, metabolisms of glucose and lipids, and vascular reactivity in LPS-exposed placenta. Many upstream regulators and master regulators important for nutrient-sensing and mitochondrial function were also altered in inflammation exposed placentae, including STAT1, HIF1α, mTOR, AMPK, and PPARα. Comprehensive quantification of metabolites demonstrated significant alterations in the glucose utilization, metabolisms of branched-chain amino acids, lipids, purine and pyrimidine, as well as carbon flow in TCA cycle in LPS-exposed placenta compared to control placenta. The transcriptome and metabolome were also integrated to assess the interactions of altered genes and metabolites. Collectively, significant and biologically relevant alterations in the placenta transcriptome and metabolome were identified in placentae exposed to intrauterine inflammation. Altered mitochondrial function and energy metabolism may underline the mechanisms of inflammation-induced placental dysfunction.
    Keywords:  bioenergetic metabolism; inflammation; metabolome; placenta; spontaneous preterm birth; transcriptome
  3. J Reprod Immunol. 2020 Nov 17. pii: S0165-0378(20)30170-4. [Epub ahead of print]143 103249
      Preeclampsia is a leading cause of maternal and offspring mortality and morbidity, and predicts increased future cardiovascular disease risk. Placental dysfunction and immune system dysregulation are likely key pathophysiological factors. Soluble human leukocyte antigen G (sHLA-G) may dampen the specific immune response towards placental trophoblasts. Previous studies have shown low sHLA-G levels in preeclampsia, but postpartum, levels are unknown. Furthermore, the relationship between sHLA-G and sFlt-1 and PlGF, placental function markers, is unknown. We hypothesized that low maternal sHLA-G during pregnancy would be associated with placental dysfunction, including preeclampsia, gestational hypertension, and dysregulated sFlt-1 and PlGF, and that sHLA-G would remain decreased following preeclampsia. We included 316 pregnant women: 58 with early-onset preeclampsia (<34 weeks' gestation), 81 with late-onset preeclampsia (≥34 weeks' gestation), 25 with gestational hypertension, and 152 normotensive controls. Postpartum (1 or 3 years), we included 321 women: 29 with early-onset preeclampsia, 98 with late-onset preeclampsia, 57 with gestational hypertension, and 137 who were normotensive during their index pregnancies. In pregnancy, plasma sHLA-G was significantly lower both in the early- and late-onset preeclampsia groups compared to controls. In women with preeclampsia or gestational hypertension, sHLA-G was inversely correlated with serum sFlt-1. Postpartum, plasma sHLA-G levels were significantly higher in women who had had early-onset preeclampsia compared to controls. Our results support that sHLA-G may be important for placental function. Unexpectedly, sHLA-G was elevated up to 3 years after early-onset preeclampsia, suggesting an excessively activated immune system following this severe preeclampsia form, potentially contributing to future cardiovascular disease risk.
    Keywords:  Angiogenic biomarkers; Immunology; PlGF; Preeclampsia; sFlt-1; sHLA-G