The function of phosphatidylinositol 3-kinase delta (PI3Kδ) enzyme in protective immunity to Trypanosoma congolense infection in mice: role of regulatory B cells
Bibliographic record
Abstract
The PI3Kδ protein is an integral component of Phosphatidylinositol 3 kinase (PI3K) signaling in B lymphocytes necessary for their functions of proliferation and metabolism. Trypanosoma species utilize mechanisms targeted at evading host B cells and antibody responses which are critical for immunity. In this project, we sought to determine the impact of PI3Kδ in immunity to Trypanosoma congolense infection in mice. Infection of p110δD910A mutant mice with T.congolense show a surprisingly enhanced control of parasitemia in early infection (7-9 days post-infection), when compared with the relatively resistant C57BL/6 (WT) mice. The mutant mice also showed a delay in B cell activation (CD86, CD80), germinal centre formation and generation of polyclonally-activated B cells (PCB). Interestingly, drug treatment of C57BL/6 with a p110δ specific inhibitor Idelalisib, to generate partial inhibition of the PI3Kδ resulted similarly in improved control of parasitemia in early disease consistent with genetically-deficient p110δD910A mice. Idelalisib treatment also delayed B cell activation of CD80/86 and reduced PCB yet resulted in normal germinal centres. Analysis of cytokine levels in the blood and peritoneal cavity showed a significantly higher proinflammatory (IFN) and lower anti-inflammatory (IL10) environment in the treated group was correlated with lower parasite load in the mice. Further analysis showed that the pattern for lower IL10 production was from specific B cells subsets with regulatory functions (B1) cells in the peritoneal cavity in the treated group compared to the WT. Similarly, we observed increased nitric oxide production which correlated with increased parasite killing in early infection in the treated group. Despite the improved early parasite control, there was a 100% mortality in the genetic mutants (p110δD910A) and 25% mortality in the Idelalisib treated group presumably due to compromised generation of parasite-specific antibodies. In conclusion, our findings suggest that PI3Kδ has both regulatory functions affecting the initial innate immune response necessary for the early control of trypanosomiasis and subsequently critical functions in generating protective antibodies necessary for long term parasite control and survival. These findings may provide insights into potential pathways that could be targeted to modulate immunity to trypanosome infections and may impact the ongoing search for an effective therapy for the disease.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 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".