Manipulating the innate and adaptive immune responses to develop novel therapies for «Aspergillus fumigatus» pulmonary infections
Notice bibliographique
Résumé
The ubiquitous mold Aspergillus fumigatus is the causative agent of a wide range of diseases consisting of invasive and non-invasive pulmonary infections that are associated with a high rate of mortality. Immunosuppressed patients are at high risk of developing invasive pulmonary aspergillosis, characterized by a progressive necrotizing pneumonitis which, if untreated, can disseminate to other organs. Patients with impaired lung function, such as those with cystic fibrosis, are at high risk of developing a chronic non-invasive infection of the airways that is associated with declining lung function, frequent hospitalizations and a high rate of mortality. Current therapeutics for both manifestations of pulmonary aspergillosis have been disappointing due to their inability to eradicate non-invasive airway infections and their poor response rate in patients with invasive infections. As immunocompetent individuals are protected against A. fumigatus disease, immunotherapies are promising solutions for the prevention or treatment of Aspergillus disease. The overarching goal of this thesis is to investigate the immune response to non-invasive and invasive A. fumigatus infection in order to develop new therapies for these conditions. Studies of the host response to non-invasive pulmonary infections have been limited by the lack of an animal model for non-invasive infection. The first specific aim of this thesis builds on the development of a model of non-invasive airway infection to investigate the role of IL-1 signaling during a non-invasive A. fumigatus infection. We demonstrate that the absence of IL-1 signaling results in increased susceptibility to A. fumigatus airway infection associated with reduced number of pulmonary neutrophils and lower levels of production of G-CSF in infected lungs. Neutrophils lacking IL-1 signaling were found to undergo accelerated apoptosis leading to reduced viability and antifungal activity. Supplementation with G-CSF suppressed these neutrophil defects in vitro and restored pulmonary neutrophil recruitment and the resistance of IL-1 receptor knockout mice to A. fumigatus to wild-type levels. These studies establish a novel role for IL-1-dependent G-CSF in maintaining neutrophil viability during pulmonary Aspergillus infection. The second specific aim of this thesis focuses on the role of adaptive immunity in protection against invasive aspergillosis through the study of a novel glycoconjugate vaccine against A. fumigatus. In collaboration with investigators at the University of Alberta, we developed a glycoconjugate vaccine that generates a specific immune response against the galactofuranose side chain of the fungal cell wall polysaccharide galactomannan (TT-Galf4). Immunization with TT-Galf4 improves survival of immunocompetent mice following systemic challenge and neutropenic mice following pulmonary challenge with A. fumigatus. Although TT-Galf4 immunization elicits high level antibody production, polyclonal and monoclonal antibody transfer studies as well as experiments in B-cell deficient mice revealed that TT-Galf4-mediated immunity is antibody independent. The studies in this thesis explore the mechanisms of host resistance to invasive and non-invasive A. fumigatus infections. The first project sheds light on mechanisms of innate immunity during A. fumigatus airway infection, while the second project lays the groundwork for the development of a novel glycoconjugate vaccine for invasive aspergillosis.
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 ».