<i>Entamoeba histolytica</i> Stimulates the Release of the Alarmin Molecule HMGB1 by a PI3 Kinase Dependent Mechanism
Bibliographic record
Abstract
The enteric protozoan parasite Entamoeba histolytica ( Eh ) is responsible for the development of amebiasis in humans. In ~90% of cases, Eh resides in the intestinal lumen asymptomatically and for unknown reasons this asymptomatic relationship breaks down and parasites invade the underlying colonic mucosa. Host pro‐inflammatory responses induced by the Eh are critical in disease pathogenesis but the exact underlying mechanisms of this response is poorly understood. Contact between Eh and macrophage triggers a raging pro‐inflammatory response by activating NLRP3 inflammasome (IL‐1β) and other uncharacterized pathways (TNF‐α) but it is not clear how non‐contacted bystander immune cells sense invasive Eh. High Mobility Group Box 1 protein (HMGB1) is a critical mediator of inflammation during infection and to shape the magnitude and degree of the inflammatory response. HMGB1 is a non‐histone nuclear protein, which have overlapping binding side with histone H1 in the chromatin. It is released in the extracellular space during infection by activated or damaged immune cells and act as an alarmin molecule. In this study, we identified HMGB1 as the earliest alarmin signals released by Eh ‐contacted macrophages that can cross talk with bystander immune cells. Human monocytic cell line (THP‐1) and mouse bone marrow derived macrophages (BMDMs) were treated with live Eh and Eh components and western blotting was used to detect HMGB1 secretion. Stimulation with live Eh but not Eh components triggered robust time‐dependent (as early as 5 minutes) secretion of HMGB1. Early release of HMGB1 by macrophages was actively secreted and independent of cell death as quantified by the detection of acetylated HMGB1 by immunoprecipitation studies and translocation of HMGB1 from the nucleus to the cytoplasm by confocal microscopy. Two major virulent factors of Eh were critical for HMGB1 protein secretion , the Gal‐lectin surface adhesin and cysteine protease 5 ( Eh CP5). Eh coupling to macrophages via the Gal lectin and Eh CP5 induced the release of HMGB1 by a PI3 kinase dependent mechanism. NLRP3 inflammasome activation was not a prerequisite for HMGB1 secretion as similar results were obtained using BMDMs from caspase‐1 −/− mice. Our results have identified that HMGB1 release is the earliest innate response upon Eh contact with macrophages that serve as a danger signal to sense parasite invasion and to signal bystander cells to enhance inflammation in innate host defense against amebiasis. Support or Funding Information Grant Support: NSERC
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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) | 0.003 | 0.001 |
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".