A292 NLRP 3-DEPENDENT PRODUCTION OF ANTIMICROBIAL PEPTIDES DURING CO-INFECTION WITH GIARDIA INTESTINALISAND E. COLI
Bibliographic record
Abstract
Infectious diarrheal disease represents a critical concern for child health in developing countries. Recent findings indicate that in such environments, infection with Giardia intestinalis may protect against bacterial driven diarrhea via mechanisms that remain unknown. We hypothesized that cysteine protease(s) released by Giardia in co-infection with enteropathogenic Escherichia coli (EPEC) activate the NLPR3 inflammasome pathway, increasing antimicrobial peptides (AMPs) production and secretion. Mice (wild type or NLRP3 -/-) were infected with G. muris and/or Citrobacter rodentium to model co-infections with Giardia and EPEC in humans. AMP production, bacterial pathogen burdens, and colonic disease activity were assessed. Human enterocytes (Caco-2) were pretreated or not for 30 min with glyburide (NLRP3 inhibitor; 100 mm), and infected with Giardia duodenalis trophozoites (with or without pre-treatment with cathepsin B inhibitors) and EPEC separately or in combination. Human β-defensin-2 (HBD-2) and trefoil-factor 3 (TFF3) protein and mRNA expression were assessed by immunofluorescent (IF) staining and by RT-qPCR, respectively. Infection with G. muris increased colonic levels of murine β-defensin and TFF3, inhibited bacterial colonization, and reduced disease activity in co-infected animals. The effects were lost in NLRP3 -/- mice. IF staining intensity of HBD-2 and TFF3 was the highest in co-infected epithelial cells, compared to EPEC-infected only. The effects were reversed by the administration of the NLRP3 inhibitor. HBD-2 and TFF3 mRNA levels were increased in the co-infected caco-2 cells, as compared to cells infected only with EPEC, also in a NLRP3-dependent manner. Pre-treatment of Giardia trophozoites with a selective cathepsin B inhibitor abolished the effects of G. intestinalis. Co-infection in vitro also reduced bacterial numbers retrieved after the experiment compared with bacterial numbers retrieved from the cells infected only with EPEC. Moreover, G. intestinalis directly inhibited EPEC growth in vitro, in a cathepsin B-dependent manner. Our data suggest novel mechanisms involved in the production of antimicrobial peptides. Giardia co-infection with EPEC activates expression and secretion of AMPs in human intestinal epithelial cells through activation of the NLRP3 pathway. Giardia cathepsin B-like proteases participate in this effect, which protects an infected host during co-infections with bacterial enteropathogens like EPEC. CIHR
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".