Identification of candidate Toxoplasma gondii factors that are responsible for the inhibition of interferon gamma mediated up-regulation of major histocompatibility complex class-II
Bibliographic record
Abstract
The obligate intracellular pathogen Toxoplasma gondii is one of the most successful pathogens in the world, with an average worldwide infection rate of ~30 % in humans. The ability of the T. gondii to establish persistent infections in immunocompetent hosts is likely due to its immune evasion strategies that include interference with T cell activation, blocking of pro-inflammatory cytokine signaling while stimulating anti-inflammatory signaling and preventing the expression of major histocompatibility complex class II (MHC-II) molecules by immune cells. This blocking the production of MHC-II by professional antigen presenting cells dampens the CD4+ T cell response and delays the onset of cellular immunity, thereby allowing T. gondii to establish a lifelong chronic infection. Infection of professional antigen presenting cells with live parasites and exposure to parasite lysate both result in a blockage of IFN-gamma dependant MHC-II production and surface expression. However, the mechanisms of inhibition by live parasites differ from those observed with parasite lysates suggesting multiple and non-redundant mechanisms of MHC-II expression inhibition during a T. gondii infection. The active molecules from parasite lysates likely represent proteins secreted by the parasite that act on host cells even prior to their infection. The parasite molecule(s) responsible for this important immune evasion mechanism remain(s) unknown. In our studies, we used sub-cellular fractionation and chromatographic techniques to isolate and enrich for the protein(s) responsible for interfering with IFN-gamma dependant MHC-II production. Preliminary experiments demonstrated that the active component was a soluble protein. Sub-cellular fractionation experiments indicated that inhibition levels corresponded to the amount of dense granules, a specialized T. gondii secretory organelle, present in the fractions. We also demonstrated that extracellular parasites actively secrete proteins and that these excretory-secretory antigens (ESA) contain MHC-II expression inhibiting molecule(s). Size-exclusion chromatography of soluble parasite lysate and ESA indicated MHC-II expression inhibiting molecules were present in fractions representing a large size range of proteins. Most of these molecules were however confined to the fractions containing the largest proteins and/or protein complexes. To isolate the active molecules, a two-step fractionation process was devised. ESA proteins were first subjected to anion-exchange chromatography and the fraction presenting the greatest abundance of MHC-II expression inhibition was then further separated by size-exclusion chromatography for isolation and enrichment of active molecule(s). The latter separated the active molecule(s) into two fractions. LC-MS/MS analysis of these fractions identified 24 candidate Toxoplasma gondii proteins responsible for the inhibition of MHC-II expression in bone marrow derived macrophages.
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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".