Cellular and molecular mechanisms of helminth-induced immunomodulation
Bibliographic record
Abstract
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.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".