Toxoplasma gondii infection inhibits invasion and migration of human extravillous trophoblasts through dysregulation of FOXO1- and FOXO3a-dependent and -independent mechanisms
Bibliographic record
Abstract
The protozoan parasite Toxoplasma gondii causes severe pathologies in the infected fetus following vertical transmission during pregnancy. Primary T. gondii infection increases the risk of miscarriage during the first trimester of gestation; however, the cellular and molecular mechanisms are not fully understood. Extravillous trophoblasts (EVTs) are fetal cells that migrate and invade the maternal decidua to allow placenta formation and embryo implantation. The transcription factors Forkhead box O3a (FOXO3a) and FOXO1 play a central role in the regulation of EVT migration and invasion. Hence, impairment of EVT functions is associated with FOXO3a/FOXO1 dysregulation and poor pregnancy outcomes. Interestingly, T. gondii -driven inactivation of FOXO3a and FOXO1 was reported in fibroblasts and macrophages. Using a combination of cell imaging, reverse genetics and biochemical approaches in the human trophoblast cell line HTR-8/SVneo, herein we provide evidence that infection with type I RH T. gondii strain inhibits invasiveness and migratory activities in EVTs by repressing FOXO3a-and FOXO1-dependent and independent gene expression. Indeed, either T. gondii infection or single knockdown of FOXO3a and FOXO1 reduced invasion and migration properties in EVTs. Selective chemical blockade of parasite motility and host cell entry indicates that active infection is indispensable for reduced EVT migration but is only partially required for T. gondii -driven repression of EVT invasiveness. Mechanistically, T. gondii infection led to AKT-sensitive phosphorylation and nuclear exclusion of FOXO3a and FOXO1 in EVTs. An RT-qPCR-based screening identified a subset of invasion-and migration-associated genes downregulated in T. gondii -infected EVTs (MMP2, MMP3, MMP14, TIMP2, MUC1, and ITGB3). Transcription of genes encoding MMP3 and integrin β3 decreased in FOXO3a KD and FOXO1 KD EVT cell lines, respectively. These data along with pharmacological inhibition of AKT in infected cells provide evidence that T. gondii downregulates MMP3 and ITGB3 gene expression in EVTs in an AKT-FOXO3a/FOXO1-dependent fashion. In all, we have uncovered a novel regulatory mechanism involved in the repression of EVT migration and invasion properties during T. gondii infection. Further investigation using in vivo and ex vivo models of placental infection is required to determine whether T. gondii -driven dysregulation of EVT functions contributes to pregnancy complications associated with congenital toxoplasmosis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".