Polyphosphatases have a polyphosphate-independent influence on the virulence of <i>Cryptococcus neoformans</i>
Bibliographic record
Abstract
ABSTRACT Cryptococcus neoformans, an invasive basidiomycete fungal pathogen, causes one of the most prevalent, life-threatening diseases in immunocompromised individuals and accounts for ~19% of AIDS-associated deaths. Therefore, understanding the pathogenesis of C. neoformans and its interactions with the host immune system is critical for developing therapeutics against cryptococcosis. Previous studies demonstrated that C. neoformans cells lacking polyphosphate (polyP), an immunomodulatory polyanionic storage molecule, display altered cell surface architecture but unimpaired virulence in a murine model of cryptococcosis. However, the relevance of cell surface changes and the role of hyperaccumulation of polyP in the virulence of C. neoformans remain unclear. Here we show that mutants with abundant polyP due to loss of the polyphosphatases Xpp1 and Epp1 are attenuated for virulence. The double mutant differed from the wild type during disease by demonstrating a higher fungal burden in disseminated organs at the experimental endpoint and by provoking an altered immune response. An analysis of triple mutants lacking the polyphosphatases and the Vtc4 protein for polyP synthesis also caused attenuated virulence in mice, thus suggesting an influence of Xpp1 and/or Epp1 independent of polyP levels. A more detailed characterization revealed that Xpp1 and Epp1 play multiple roles by contributing to the organization of the cell surface, virulence factor production, the response to stress, and mitochondrial function. Overall, we conclude that polyphosphatases have additional functions in the pathobiology of C. neoformans beyond an influence on polyP levels. IMPORTANCE Cryptococcus neoformans causes one of the most prevalent fungal diseases in people with compromised immune systems and accounts for ~19% of AIDS-associated deaths worldwide. The continual increase in the incidence of fungal infections and limited treatment options necessitate the development of new antifungal drugs and improved diagnostics. Polyphosphate (polyP), an under-explored biopolymer, functions as a storage molecule, modulates the host immune response, and contributes to the ability of some fungal and bacterial pathogens to cause disease. However, the role of polyP in cryptococcal disease remains unclear. In this study, we report that the polyphosphatase enzymes that regulate polyP synthesis and turnover contribute to the virulence of C. neoformans in a mouse model of cryptococcosis. The polyphosphatases influenced the survival of C. neoformans in macrophages and altered the host immune response. In addition, the mutants lacking the enzymes have changes in cell surface architecture and size, as well as defects in both mitochondrial function and the stress response. By using mutants defective in the polyphosphatases and polyP synthesis, we demonstrate that many of the phenotypic contributions of the polyphosphatases are independent of polyP.
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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".