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Hypoxia-Inducible Factor 1 Alpha Is Dispensable for Host Defense of Group B Streptococcus Colonization and Infection.

ABSTRACT: Group B Streptococcus (GBS) is a leading cause of neonatal morbidity and mortality, and the primary source of exposure is the maternal vagina. Intrapartum antibiotic prophylaxis for GBS-positive mothers has reduced the incidence of GBS early-onset disease, however, potential long-lasting influence of an antibiotic-altered neonatal microbiota, and the frequent clinical sequelae in survivors of invasive GBS infection, compels alternative treatment options for GBS. Here, we examined the role of transcription factor hypoxia-inducible factor 1 alpha (HIF-1α), widely recognized as a regulator of immune activation during infection, in the host response to GBS. Given the importance of endogenous HIF-1α for innate immune defense, and the potential utility of HIF-1α stabilization in promoting bacterial clearance, we hypothesized that HIF-1α could play an important role in coordinating host responses to GBS in colonization and systemic disease. Counter to our hypothesis, we found that GBS infection did not induce HIF-1α expression in vaginal epithelial cells or murine macrophages, nor did HIF-1α deficiency alter GBS colonization or pathogenesis in vivo. Furthermore, pharmacological enhancement of HIF-1α did not improve control of GBS in pathogenesis and colonization models, while displaying inhibitory effects in vaginal epithelial cytokines and immune cell killing in vitro. Taken together, we conclude that HIF-1α is not a prominent aspect of the host response to GBS colonization or invasive disease, and its pharmacological modulation is unlikely to provide significant benefit against this important neonatal pathogen.

SUBMITTER: Lum GR

PROVIDER: S-EPMC8613573 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesHIF2α is of vital importance in the regulation of endothelial dysfunction, cell proliferation, migration, and pulmonary vascular remodeling in pulmonary hypertension. Our previous studies demonstrated that conditional and inducible deletion of HIF2α in mouse lung endothelial cells, dramatically protected the mice against vascular remodeling and the development of pulmonary arterial hypertension (PAH). Here, we provide a novel transcriptome insight into the impact of HIF2α in PAH pathogenesis and the potential to use HIF2α-mediated gene sets to differentiate PAH human subjects.MethodsUsing transcriptome data, we first tapped the value of the difference in gene expression profile between wild type (WT) and Hif2a knockdown (KD) cell lines. We considered the deregulated genes between WT and Hif2a-KD cells as HIF2α influenced genes. By examining the lung tissue transcriptome data set with nine controls and eight PAH patients, we evaluated the HIF2α regulatory network in PAH pathogenesis to further determine the identification ability of HIF2α-mediated gene sets in human PAH subjects. On the other hand, using peripheral blood mononuclear cells (PBMCs) transcriptome data from PAH patients and healthy controls, we further validated the potential of the HIF2α-mediated PBMC gene sets as a possible diagnostic tool for PAH. To verify the ability of HIF2α-mediated gene sets for the identification of PAH, endothelial cell-specific Phd2 knockout mice with spontaneous pulmonary hypertension were used for reverse validation experiments.Results19 identified GO biological process terms were significantly correlated with the genes down-regulated in Hif2a-KD cells, all of which are strongly related to the PAH pathogenesis. We further assessed the discriminative power of these HIF2α-mediated gene sets in PAH human subjects. We found that the expression profile of the HIF2α-mediated gene sets in lung tissues and PBMCs were differentiated both between controls and PAH patients. Further, a significant positive correlation was observed between hypoxia and Phd2 deficiency mediated gene set expression profiles. As expected, 7 of the 19 significantly down-regulated GO terms in Hif2a-KD cells were found to overlap with the up-regulated GO gene sets in Phd2 EC-/- mice compared to WT controls, suggesting opposing effects of HIF2α and PHD2 on PAH pathogenesis.ConclusionHIF2α-mediated gene sets may be used to differentiate pulmonary arterial hypertension.

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Hypoxia-Inducible Factor 1 Alpha Is Dispensable for Host Defense of Group B Streptococcus Colonization and Infection.

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