A298 A SWITCH FROM MUC2 TRANSCRIPTION TO MUC5AC IS A COMPENSATORY MECHANISM AGAINST THE MUCOLYTIC ACTIVITY OF GIARDIA DUODENALIS
Notice bibliographique
Résumé
Giardia duodenalis is a diarrheagenic parasite of the small intestine characterized by acute and chronic illnesses including irritable bowel syndrome. MUC5AC mucin in the stomach and MUC2 in the intestine are normally protective against pathogens. We hypothesized that Giardia is able to disrupt this barrier by several mechanisms that may contribute to both acute and chronic disease. Muc2-/- (KO-inf) and C57BL/6 (WT-inf) mice were gavaged with Giardia trophozoites and euthanized on day 7. Tissues were collected for histological staining, qPCR, and analysis of bacterial translocation. Human colonic biopsies were exposed to Giardia trophozoites to quantify intracellular mucins. In vitro, Giardia trophozoites were incubated with or without a cysteine protease inhibitor, E64, then with a human mucus-producing cell line, LS174T, to assess intracellular mucin content and MUC2 transcription. Giardia’s secreted products were incubated with purified human MUC2 to assess proteolysis via western blot. KO-inf mice had a higher parasitic load compared to WT-inf mice and failed to gain weight over the period of infection. Compared to non-infected mice, WT-inf mice exhibited novel transcription of Muc5ac and decreased transcription of Muc2 in the jejunum. Both Muc2 and Muc5ac mRNA were increased in the colon. Of note, Muc5ac transcription was not induced in KO mice. WT-inf mice had larger colonic mucus granules but a thinner mucus layer, demonstrated by staining with periodic-acid Schiff/Alcian blue, wheat germ agglutinin, and with the use of microbiota markers using fluorescent in situ hybridization. Infected mice had increased aerobic and anaerobic bacterial translocation into the liver and spleen. In vitro, Giardia’s secreted products degraded human MUC2. This was attenuated by E64. Human biopsies exposed to Giardia had less intracellular mucus granule content. Giardia reduced intracellular mucin content in LS174T cells after 20, 40, and 60 minutes post-infection (also inhibited by E64), whereas it increased mucin content by 3 hours post-infection. In vitro, Giardia infection increased Muc2 transcription after 1 hour. In mice, Muc2 was protective against parasite accumulation and induced weight loss, but Giardia disrupted the mucosal barrier function by reducing the mucus layer and causing an alteration of mucin gene transcription, specifically an increase of Muc5ac and a decrease of Muc2 in the jejunum. Proteolysis of MUC2 could be a potential mechanism by which Giardia alters barrier function in vivo. Resultant loss of the mucus barrier was associated with increased bacterial translocation and may contribute to both acute and chronic disease. Mucin degradation and depletion were attenuated by a cysteine protease inhibitor, indicating a potential target to reduce Giardia-induced pathology. CAGNSERC CREATE Host-Parasite Interactions
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».