Subversion of dendritic cell immunity to Cryptococcus gattii by a novel phagosomal F-actin cage structure
Bibliographic record
Abstract
The highly virulent fungus, Cryptococcus gattii, emerged as a novel respiratory pathogen on Vancouver Island (British Columbia, Canada) nearly two decades ago and has spread to the surrounding regions encompassing the Pacific Northwest of United States, where there is an ongoing outbreak. C. gattii is a major cause of life-threatening cryptococcosis in immunocompetent individuals and has a mortality rate of up to 33%. Host immune response is a key determining factor for the development of cryptococcal disease. It is now recognized that evasion of host immune recognition is a hallmark of C. gattii pathogenesis, but the mechanism of immune evasion remains unclear. There is increasing evidence that C. gattii subverts dendritic cell (DC) activation to evade the protective T helper cell-mediated immunity. This thesis demonstrates that primary human DC can phagocytose C. gattii yeasts but trafficking to the late phagolysosome is blocked by retention of a filamentous actin (F-actin) cage on the phagosomes. Structural studies by super resolution microscopy revealed a novel, highly branched F-actin cage that physically interfered with lysosomal fusion. C. gattii F-actin cage promoted immune evasion by silencing the canonical RelA signaling of the NF-κB pathway required for DC costimulation and T cell activation. Disruption of the F- actin cage through targeted inhibition or by TNF-α signaling reprogrammed quiescent DC to immunocompetent antigen-presenting cells (APCs). Furthermore, the presence of phagosomal F-actin cage corresponded with the presence of C. gattii polysaccharide capsule. Acapsular mutant strains did not retain phagosomal F-actin and were remarkable at inducing DC activation and T cell proliferation. Collectively, our results have uncovered a unique mechanism of DC immune subversion by intracellular pathogens such as hypervirulent C. gattii. Manipulations of this mechanism can potentially inform novel therapeutic interventions against C. gattii.
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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) | 0.000 | 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".