Manipulating the innate and adaptive immune responses to develop novel therapies for «Aspergillus fumigatus» pulmonary infections
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".