Molecular studies of mycobacterium tuberculosis complex (MTBC) virulence
Notice bibliographique
Résumé
The Mycobacterium tuberculosis complex subspecies (MTBCs) are closely related pathogens causing tuberculosis in mammalian hosts. Research has predominantly focused on Mycobacterium tuberculosis (M. tb, the causative agent of human tuberculosis) and Mycobacterium bovis (M. bovis, a causative agent of zoonotic tuberculosis). Notably, M. tb is a human-adapted pathogen whereas M. bovis is an animal-adapted member of the MTBC. Foundational work by Robert Koch and Theobald Smith established that M. tb and M. bovis have significantly different infection outcomes, with M. bovis infection resulting in more severe pathology in experimental infections. Globally, more than 10 million new cases of TB are reported each year; ~1% are estimated to be due to zoonotic tuberculosis (zTB), typically attributed to M. bovis. However, recent studies have highlighted that another organism, Mycobacterium orygis, may also contribute to the global TB burden. As this organism was first characterized in 2012, it has not been subject to thorough experimental investigation and as such, knowledge on its epidemiology and pathogenesis are limited. Current molecular tools have enabled researchers to translate natural observations from clinics into systematic evaluations in the laboratory, using in vitro, ex vivo, and in vivo techniques. To this end, in this thesis, I used mycobacterial engineering to develop isogenic strains of M. bovis Bacille Calmette-Guérin (BCG), M. bovis, and M. orygis. BCG strains were subsequently employed in clinical diagnostics whereas M. bovis and M. orygis isogenic strains were used to investigate infection outcomes using both ex vivo and in vivo models.In chapter II, I developed a panel of 6 mono-resistant strains of the attenuated BCG vaccine using oligo-mediated recombineering for laboratory quality control studies. In chapter III, I used the ORBIT (oligo-mediated recombineering followed by Bxb-1 integrase targeting) system to develop 8 deletion strains targeting either the canonical virulence factor ESAT-6, or the non-canonical virulence factors MPT70/MPT83 (in M. bovis and M. orygis) and characterized their effects on protein secretion and macrophage infection. In chapter IV I used a murine infection model to characterize the experimental outcome following aerosol exposure to M. tb, M. bovis, and for the first time, M. orygis, revealing that M. bovis and M. orygis are hypervirulent compared to M. tb following infection of the same host (based on comparative pathology, median survival, and lethal dose). Additionally, I established that MPT70/MPT83 are critical virulence factors in M. bovis but not M. orygis in this model. It was also observed that rapid mortality seen following M. orygis infection could be delayed, but not overcome, by vaccination with either BCG (a live, attenuated vaccine) or novel subunit vaccines. Finally, in chapter V I, in conjunction with researchers at the University of Saskatchewan, determined that M. bovis and M. orygis show significantly worse experimental outcomes compared to M. tb in a calf model of infection. Ultimately, this dissertation provides novel insights into the MTBCs and utilizes in vitro, ex vivo, and in vivo techniques to experimentally characterize M. orygis for the first time. This thesis established two recombineering systems in animal-associated lineages of the MTBCs and the products of the tools have been used in both clinical and research laboratories. Perhaps most importantly, this thesis has provided evidence that a third species should be considered in future pathogenesis research and may be used as a new ‘foundation’ for the study of MTBC virulence factors
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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 ».