Identification of a phagosomal F-actin structure that evades dendritic cell immunity to <i>Cryptococcus gattii</i>
Bibliographic record
Abstract
Abstract Hypervirulent Cryptococcus gattii is a major cause of life-threatening cryptococcosis in immunocompetent individuals and responsible for the ongoing outbreak in the Pacific Northwest. This deadly fungus is known to subvert dendritic cell (DC) maturation and concomitant T cell immunity via immune evasion mechanisms that are poorly understood. Here, we show that primary human DC can phagocytose endemic yeasts but trafficking to the late phagolysosome is blocked by retention of a filamentous actin (F-actin) cage surrounding the phagosomes. Structural studies by super resolution microscopy revealed a novel highly branched F-actin cage that physically interfered with lysosomal fusion. Mechanistically, we demonstrate that C. gattii F-actin cage promotes 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) and revealed the existence of a negative feedback loop between periphagosomal F-actin aggregation and pro-inflammatory NF-κB signaling. Collectively, our results have uncovered a unique mechanism of DC immune subversion by organisms such as hypervirulent C. gattii and revealed the potential clinical significance of the immunomodulatory function of phagosomal F-actin in host-pathogen interaction.
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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".