«Leishmania»-macrophage interactions: regulations of protein tyrosine phosphatases and its implication in the outcome of infection
Bibliographic record
Abstract
The outcome of Leishmania infection depends both on host and pathogen factors. Macrophages, the specialized host cell for uptake and intracellular development of Leishmania parasites, play a central role in the control of infection. Underlying their effector and accessory functions is the activation of signalling pathways, which in turn are largely controlled by events of protein phosphorylation. Consequently, the regulation of protein kinase and phosphatase activities results critical for the sequential progression of the signalling cascade, and therefore for the control of antimicrobial and inflammatory phagocyte functions. This doctoral thesis discusses novel mechanisms of protein tyrosine phosphatase (PTP) regulation in the context of Leishmania-macrophage interactions. Herein are presented two events in which, independently, host and pathogen factors orchestrate the differential regulation of macrophage PTP activity. Chapter 2 describes the role of NRAMP-1 on macrophage PTP activity modulation. These investigations led to discover that iron, a metal substrate of NRAMP-1, inhibits PTP activity, resulting in the upregulation of leishmanicidal macrophage functions, through the positive regulation of JAK/STAT and MAPK signalling. Furthering these observations, an in depth study of the mechanisms underlying iron-dependent PTP inhibition (presented as Chapter 3), identified mononuclear dicitrate iron citrate complexes as specific PTP inhibitors. Despite the role of macrophages as efficient accessory and effector immune cells, Leishmania has evolved strategies to downregulate host cell functions. This is largely mediated by the parasite-induced activation of macrophage PTPs. In Chapter 4 we identified PTP1B and TCPTP as two novel PTPs engaged upon Leishmania infection. More importantly, we unravel an intimate interaction between the Leishmania surface protease GP63 and host PTPs, revealing a novel mechanism of PTP cleavage-dependent activation. Collectively,
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".