Delayed viral clearance and altered inflammatory responses resulted in increased severity of SARS-CoV-2 infection in aged mice
Notice bibliographique
Résumé
Abstract Since the onset of the COVID-19 pandemic, advanced age has emerged as a major predictor of disease severity. Epidemiological investigations consistently demonstrate an overrepresentation of the elderly in COVID-19 hospitalizations and fatalities. Despite this, a comprehensive understanding of the molecular mechanisms explaining how old age constitutes a critical risk factor remains elusive. To unravel this, we designed an animal study, juxtaposing the course of COVID-19 in young adults (2 months) and geriatric (15-22 months) mice. Both groups of K18(hACE2) mice were intranasally exposed to 500 TCID 50 of the SARS-CoV-2 Delta variant with a variety of outcomes assessed on days 3, 5, and 7 post-infections (DPI). Analyses included pulmonary cytokines, RNA, viral loads, lipidomic profiles, and histological assessments, with a concurrent evaluation of the percentage of mice reaching humane endpoints. The findings unveiled notable distinctions between the two groups, with aged mice exhibiting impaired viral clearance at 7 DPI, correlating with diminished survival rates together with an absence of weight loss recovery at 6-7 DPI. Additionally, elderly-infected mice exhibited a deficient Th1 response characterized by diminished productions of IFNg, CCL2, CCL3, and CXCL9 relative to younger mice. Furthermore, mass-spectrometry analysis of the lung lipidome indicated altered expression of several lipids with immunomodulatory and pro-resolution effects in aged mice such as Resolvin, HOTrEs, and NeuroP, but also DiHOMEs-related ARDS. Collectively, disease severity implies a dysregulation of the antiviral response in elderly-infected mice relative to younger mice, resulting in compromised viral clearance and a more unfavorable prognosis. This underscores the potential efficacy of immunomodulatory treatments for elderly subjects experiencing symptoms of severe COVID-19. Author summary In this study, we investigated why older age is linked to more severe COVID-19 outcomes by comparing the progression of the disease in young (2 months) and elderly (15-22 months) K18(hACE2) mice infected with the SARS-CoV-2 Delta variant. After exposing both groups to the virus, we assessed various factors such as viral loads, immune responses, and lipid profiles in the lungs at different time points. Our findings revealed that elderly mice struggled to clear the virus by day 7 post-infection, leading to higher mortality rates and poorer recovery compared to younger mice. Aged mice showed weaker immune responses, with reduced production of key antiviral proteins like IFNg and certain chemokines. Lipid analysis also highlighted differences in molecules involved in immune regulation and lung protection, such as decreased levels of pro-resolving lipids and increased lipids associated with lung injury. These results suggest that older mice have a compromised antiviral defense, which could inform new therapeutic approaches for elderly patients with severe COVID-19.
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| 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 ».