<i>Toxoplasma</i> induced cytokine release syndrome is critically dependent on the expression of pore-forming Perforin-Like Protein-1
Bibliographic record
Abstract
Abstract Acute virulence in Toxoplasma gondii is linked to an excessive proinflammatory cytokine cascade during laboratory murine infection. Previous work showed that T. gondii secretes a pore forming protein, PLP1, that is required for efficient cytolytic egress from host cells. Deletion of the PLP1 gene results in defective egress from infected culture cells and a marked reduction in parasite virulence. The goal of the present study was to gain insight into the nature of the attenuated virulence observed in PLP1 knockout compared to wild type (WT) RH parasites. Using in vivo bioluminescence imaging, we show that parasites lacking PLP1 establish an acute infection and disseminate throughout the infected mice. Histological tissue analysis indicates that parasites cause severe pathology, even in the absence of PLP1. However, mice infected with Δplp1 parasites evoke a protective inflammatory response, demonstrated by mouse survival and control of infection. Flow cytometric analysis was used to determine cellular changes occurring during both WT and Δ plp1 parasite infection. Parasite control in the Δplp1 infection was associated with earlier activation of myeloid cells and a moderate neutrophil response that, by comparison, becomes the dominant infiltrating cell type of WT infection. Positive disease outcome during Δplp1 parasite infection is also associated with regulated induction of proinflammatory cytokines, including IFN-γ and TNF-α, and an earlier IL-10 regulatory response that is dysregulated during WT infection. Together these findings suggest a key role for Toxoplasma PLP1 in promoting a lethal inflammatory immune response during acute infection with a virulent strain of the parasite. Author Summary Pore-forming proteins are virulence determinants expressed by multiple different pathogens, with varied roles including cellular invasion and escape, immune cell destruction, and the hijack of host cell defenses. The pathogen, Toxoplasma gondii , expresses a pore-forming protein PLP1, that is required for cell lysis and acute virulence in mice. Here, we investigate the potential mechanisms by which this pore-forming protein promotes parasite virulence; from parasite replication and dissemination to immunologic outcomes after infection. In vivo infections demonstrate that parasites replicate, disseminate, and stimulate a protective immune response when PLP1 is not expressed. We show that PLP1 expression induces a parasite driven dysregulation of cell populations and cytokine/chemokine responses, resulting in cytokine release syndrome. In a broader context, Toxoplasma’s PLP1 is comparable to other pathogen pore-forming proteins that function as virulence determinants by their ability to alter host immune responses.
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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) | 0.001 | 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 | 0.001 |
| 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".