A44 STAT1 ACTS IN INNATE IMMUNE CELLS TO PREVENT LIVER PATHOLOGY FOLLOWING ASYMPTOMATIC INTESTINAL VIRAL INFECTION
Notice bibliographique
Résumé
Abstract Background In the mammalian gut, interactions between the host and commensal organisms must be regulated to prevent damage and derive benefits from these organisms. While this regulation has been well-studied in the context of bacteria, much less is known about how commensal-like viruses in the intestine are managed by the host. Evidence demonstrates that viral commensals can provide benefits to the host which supplement those from bacteria. In mice, depletion of the intestinal virome enhances susceptibility to DSS-induced colitis. Contributions of the virome can also be studied using murine norovirus strain CR6 (CR6), which forms persistent asymptomatic infections in the gut; this infection protects mice from both C. rodentium- and DSS-induced colitis. Despite these benefits, host-encoded mechanisms regulating viral commensalism remain understudied. One host-encoded mechanism is STAT1. In contrast to asymptomatic infection in wild-type mice, STAT1-deficient mice (Stat1-/-) develop severe disease characterized by liver necrosis and weight loss following CR6 infection. However, it remains unknown how the loss of STAT1 leads to CR6-induced disease. Aims We aimed to define STAT1-dependent mechanisms of protection from CR6-induced liver pathology. Methods To determine the contribution of STAT1 in protection from CR6-induced disease, Stat1-/- and STAT1-sufficient Stat1+/- littermates were infected i.v. with CR6. At days 3, 5, and 7 days post-infection, clinical disease, cell-intrinsic viral loads, pathology, and cellular infiltration were assessed. Bone marrow chimeras were used to evaluate the requirement for hematopoietic vs non-hematopoietic STAT1 in preventing disease. Results By 3 days post-infection, myeloid cells infiltrate the liver of CR6-infected Stat1-/- mice. Clinical disease is associated with accumulation of myeloid cells, including macrophage and dendritic cells in the liver . Sorting of liver-infiltrating immune cell populations revealed that Stat1-/- macrophage have elevated viral loads compared to Stat1+/- littermates (Figure). Notably, CD11b+ cells were enriched within the necrotic lesions characteristic of CR6-induced disease. Consistent with a role for innate immune cells in disease, bone marrow-derived macrophage from Stat1-/- mice failed to control viral replication in vitro. Further, bone marrow chimeras revealed that STAT1 expression in hematopoietic cells is necessary and sufficient to prevent CR6-induced disease. Together, these data suggest that in the absence of STAT1, innate immune cells become heavily infected with CR6 and mediate severe liver pathology. Conclusions Our data suggest that STAT1 is critical to maintaining a commensal relationship with the intestinal virome. In the absence of STAT1, failure to restrict the replication of viral commensal CR6 in innate immune cells leads to severe liver pathology. STAT1-deficient innate immune cells fail to control viral replication. Stat1 -/- and Stat1+/- mice were infected i.v. with CR6. 5 days post-infection, macrophage, dendritic cell, neutrophil, and monocyte populations were isolated from the liver by FACS. Viral genome copies were quantified by RT-qPCR. LoD = Limit of Detection. Mann-Whitney U test, ** = p ampersand:003C 0.01. Funding Agencies CIHR
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 | 0,001 |
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 ».