A12 STEPWISE COORDINATION OF COLONIC NEUTROPHILS AND INNATE LYMPHOID CELLS IN THE ONSET AND RESOLUTION OF CLOSTRIDIOIDES DIFFICILE TOXIN-INDUCED INJURY
Notice bibliographique
Résumé
Abstract Background While our understanding and use of treatments for Clostridioides difficile infection (CDI) has improved, initial CDI still carries significant morbidity and mortality owing to heterogeneity in host immune responses. Further, host immunity is a critical modulator of fecal microbiota transplantation (FMT) success in CDI. Thus, understanding the host immune response during CDI is essential. Aims To assess the cellular immune responses that trigger the onset and resolution of injury and inflammation in CDI. Methods Colonic injury and inflammation triggered by CDI was modelled in mice using intrarectal installation of C. difficile toxins A and B (TcdA/B). Colonic tissue was collected at various timepoints following TcdA/B exposure to assess gene expression (qPCR), cytokine production (ELISA) and immune cell responses (flow cytometry). Knockout mice and neutralizing antibodies were used to deplete cytokines or cells. Results Examinion of colonic gene expression at different times following TcdA/B exposure found a dominant transcriptional signature related to neutrophil adhesion and diapedesis. In addition to the typical neutrophil chemokines Cxcl1 and Cxcl2, TcdA/B exposure also increased expression of neutrophil effector genes including Elane (neutrophil elastase). Neutrophil influx in response to TcdA/B was a critical driver of intestinal injury as antibody-mediated depletion of neutrophils lead to significantly less damage in the colon following TcdA/B exposure. Along with neutrophil influx, there were high levels of antimicrobial gene expression in the colon after TcdA/B exposure including RegIIIγ, S100a8, and Socs3, all genes regulated by IL-22. Upon further investigation, IL-22 was a significant mediator in the host response to TcdA/B exposure as it was upregulated >150-fold in the colon and originated from type 3 innate lymphoid cells (ILC3). Further, TcdA/B exposure in IL-22-/- mice lead to significantly more colonic damage compared to wildtype (WT) mice. Subsequent screening of previously published RNAseq data from IL-22-treated mouse colonic organoids identified various upregulated proteins involved in immune regulation, including the gene Slpi that encodes a protein (secretory leukocyte peptidase inhibitor) that inhibits leukocyte proteases, including neutrophil elastase. While TcdA/B challenge robustly induced the expression of Slpi in the colon of WT mice, IL-22-/- mice failed to express increased levels of Slpi and had greater levels of neutrophil elastase activity in the colon. Conclusions Together these data suggest a stepwise immune response to TcdA/B where ILC3 produce IL-22 to induce epithelial release of SLPI that attenuates the damaging effects of early neutrophil responses. Strategies to upregulate IL-22 may help control damage triggered by CDI and promote resolution of injury. Funding Agencies Lloyd Sutherland Chair in GI Research, Canadian Research Chair
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
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 ».