«Leishmania» parasites and the host macrophage: Interaction via secretion
Bibliographic record
Abstract
Protozoan parasites of genus Leishmania are the causative agents of leishmaniasis. Utilizing potent immune evasion and immune modulation mechanisms, Leishmania are able to render the host macrophage inactive and live inside its phagolysosome. Studies on the different functions of secreted vesicles, especially exosomes, which are secreted vesicles of less than 100nm in size, have now established them as an important route for cell-cell communication, in both homeostasis and pathogenesis. In this thesis, we evaluated the role of the exoproteome and exosomes in the host-parasite interactions of Leishmania. We observed that protein and exovesicle release is augmented in Leishmania mexicana following temperature shift (TS), a condition mimicking parasite's entry into its mammalian host. We next showed that TS-induced exoproteome of L. mexicana has various inhibitory properties such as induction of protein tyrosine phosphatase (PTP) activity, and inhibition of nitric oxide (NO) production. Having seen the augmentation in vesicle release in response to TS, we next specifically examined the immune modulation by Leishmania exosomes, which are secreted vesicles of smaller than 100nm in size. We compared the immunomodulatory properties of parasites and exosomes knocked out (KO) for GP63, a critical virulence factor of Leishmania, with their wildtype (WT) Leishmania major counterparts. Looking at PTPs, transcription factors, gene expression and also in vivo inflammatory recruitment, we observed that absence of GP63 results in a stronger inflammatory response to both L. major parasites and exosomes. Especially, we observed downregulation of expression of many immune receptors and adaptors following L. major infection. Also, we found WT and KO exosomes to have drastic differences in their protein content, suggesting a novel role for GP63 in exosomal protein sorting. Finally, we investigated the effect of Leishmania infection on exosome release by macrophages. For this purpose, we performed comparative proteomic analyses of exosomes released from nontreated macrophages, LPS-stimulated macrophages and L. mexicana¬-infected macrophages. We observed that Leishmania infection and LPS stimulation induce similar and also distinct alterations in the sorting of different protein functional groups into exosomes, especially those associated with the plasma membrane. These alterations can potentially change the effector functions as well as targeting of exosomes. Consequently, we observed that these exosomes differentially induce signaling molecules such as MAP Kinases in naive macrophages. Overall, we provide a new insight on the role of exosomes in the Leishmania host-parasite interactions, especially in the establishment of infection. We also expanded the understanding of the immune modulation mechanisms by Leishmania GP63. Our results deepen the knowledge regarding leishmaniasis and pave the way for development of new therapeutics.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 teacher head, 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".