A60 INVESTIGATING THE ROLE OF NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN (NOD) PROTEINS DURING BACTERIAL INFECTIONS IN INTESTINAL EPITHELIAL CELLS
Notice bibliographique
Résumé
Abstract Background Inflammatory bowel disease (IBD) is a collection of conditions that result in the inflammation of the gastrointestinal tract causing diarrhea, abdominal pain, weight loss, nausea, and vomiting. With its prevalence a whopping 0.6% in Canada, there is a need to understand the targets of therapy for the disease. Crohn’s disease, which is one of the two main conditions implicated in IBD, is most often associated with polymorphisms in the NOD2 gene. NOD2 is integral to the innate immune system of mammals, and functions as a pattern recognition receptor within the cytosol of cells. It detects conserved bacterial peptidoglycans to elicit an anti-microbial response by activating the nuclear factor kappa B pathway. NOD proteins also tackle infections upon bacterial recognition by recruitment of autophagy proteins allowing for the degradation of invading bacteria. Given their roles in bacterial clearance, it is unsurprising that mice deficient for NOD1 or NOD2 show increased susceptibility to pathogens, which is also what is thought to occur with Crohn's disease patients. Aims Although NOD1 and NOD2 have been well characterized in immune cells, little research has been done to interrogate their role during bacterial dysbiosis in intestinal epithelial cells. This research aims to elucidate the global signaling landscape that these proteins modulate in intestinal epithelial cells post-infection. We hypothesize that NOD1 and NOD2 play a critical role in host defense against intracellular bacterial pathogens in intestinal epithelial cells. Methods Intestinal crypts were harvested from WT, Nlrc4-/-, and Nlrc4-/- Ripk2-/- C57BL/6 mice to generate primary ileal organoids. Organoids infected with Shigella flexneri were harvested for protein and RNA. Downstream western blot, qPCR, Immunohistochemistry, and CFU analyses were performed to ensure the efficacy of the infection. Results Upon Shigella flexneri infection, CFU counts were only able to be recorded in a non-pyroptotic background (Nlrc4-/-). When examining the organoids by Immunohistochemistry, Shigella was well visualized in the Nlrc4-/- enteroids and was absent in WT controls 4 hours post-infection. Additionally, an increase in pro-inflammatory and stress genes was seen only in Nlrc4-/- organoids compared to WT controls. Finally, Nlrc4-/- Ripk2-/- organoids experience higher bacterial loads by CFU analysis compared to Nlrc4-/-Ripk2+/+ organoids. Conclusions Our research has shown that NOD1 and NOD2 deficiencies in primary mouse epithelial cells have increased bacteria loads compared to WTs upon infections showcasing a novel epithelial-intrinsic role for NOD1 and NOD2. This new insight into an epithelium-intrinsic role may be a step towards understanding the mechanism behind NOD2-associated Crohn's disease pathogenesis. Funding Agencies CIHRCrohn's and Colitis Canada
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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 ».