Cellular and molecular mechanisms of helminth-induced immunomodulation
Notice bibliographique
Résumé
About a third of the world’s population is infected with gastrointestinal (GI) nematodes that cause high morbidity in the developing world. As a result of host-parasite co-evolution, helminths evolved strategies to modulate host immunity to prevent their elimination and to induce minimal pathology in the host. Heligmosomoides polygyrus bakeri (Hpb), a murine GI nematode, is one of the most widely used models to study host-parasite interactions. Primary Hpb infection is chronic in some inbred mouse strains, but the mechanism(s) is unclear. Adult worms secrete excretory-secretory molecules (HES) that induce regulatory T cells (Treg) and tolerogenic dendritic cells (Tol DC), which in turn, are thought to suppress immune responses to unrelated antigens, including pathogens. Challenge infection after anthelminthic treatment results in the clearance of adult worms due to a highly polarized Th2 immune response characterized by IL-4-producing CD4+GATA3+ Th2 cells, B cell production of parasite-specific IgG1, and alternatively activated macrophages (AAM).The overall aim of this Ph.D. project was to use Hpb as an experimental model to understand the cellular and molecular mechanisms by which helminths induce immunomodulation. To understand the evasion strategies employed by GI nematodes to establish chronic infections, we first investigated the mechanism(s) involved in the establishment of chronic Hpb infection in B6 mice. We observed significant increases in F4/80-CD11b+Gr1hiLy6G+Ly6C+ myeloid-derived suppressor cells (MDSC) in mesenteric lymph nodes and spleen early after primary but not after challenge infection. MDSC from infected B6 mice suppressed antigen-specific CD4+ T cell proliferation via a nitric oxide-dependent mechanism as well as IL-4 secretion. Adoptive transfer of MDSC from infected B6 mice resulted in high adult worm burdens and increased egg production in naïve recipients. These findings indicate that primary Hpb infection induces MDSC that suppress Th2 responses and promote chronic infection. To further understand the role of MDSC during Hpb infection, we next investigated the role of the transcription factor, interferon regulatory factor 8 (IRF-8), which plays an important role in myeloid cell development. Irf8-/- mice and BXH-2 mice, a recombinant inbred strain that carries a point mutation in the Irf8 gene, have uncontrolled expansion of CD11b+Gr1+ MDSC. Irf8-/- and BXH-2 mice had significantly lower numbers of Th2 cells and AAM in lymphoid tissues and higher worm burdens compared to B6 mice during primary and challenge Hpb infections. In vitro co-culture of MDSC from Irf8-/- mice suppressed CD4+ T cell proliferation and antigen-specific IL-4 secretion. In vivo depletion of MDSC in Irf8-/- mice resulted in significant increases in Th2 cells and IL-4 production. These data highlight the importance of IRF-8 in the development of an adequate Th2 immune response to Hpb infection.Finally, we characterized HES to identify the immunosuppressive component(s) that modulate the antigen presenting function of DC. The immunosuppressive activity was found to be heat stable and partially resistant to proteinase K. We fractionated HES by high-performance liquid chromatography (HPLC) and evaluated the capacity of each fraction collected to suppress DC function. Mass spectrometry analyses of suppressive fractions derived from two independent HPLC rounds identified 21 and 8 proteins, 3 of which were common. Expression and purification of the proteins identified will be used to validate their immunosuppressive activity. In summary, this Ph.D. project identified novel cellular and molecular mechanisms by which Hpb modulates host immune responses. Identification of these mechanisms may lead to the development of better approaches to alleviate GI nematode infections as well as to the development of new therapeutics for use in autoimmune and inflammatory diseases in humans.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
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 ».