Résistance aux anthelminthique chez Dirofilaria immitis : mécanismes et marqueurs moléculaires
Bibliographic record
Abstract
Dirofilaria immitis is a parasitic filarial nematode of veterinary importance. It is the causative agent of dirofilariosis, a potentially fatal pulmonary infection of canids and felines. Dirofilariosis can be prevented with macrocyclic lactone (ML) chemoprophylaxis. The MLs are potent anti-parasiticides which target the invertebrate specific glutamate gated chloride channels (GluCls). The MLs bind pseudo-irreversibly to the GluCls opening the pore leading to hyperpolarization and paralysis of the neuromuscular system, impacting alimentation, locomotion, and mediation of sensory input and response. The MLs are a class of generally safe drugs and have been used as dirofilariosis chemoprophylaxis since the mid 1980s. Unfortunately, the continuous use of ML-based chemoprophylactics over the last four decades has led to the development of drug resistance. These ML-resistant D. immitis isolates are phenotypically and genotypically distinct from the wildtype susceptible populations. The aim of the thesis was to characterize potential mechanisms and molecular markers of ML resistance in D. immitis. For the first objective I developed of an in vitro colorimetric enzymatic activity assay based on the concept that MLs act on the microfilariae (mf) by paralyzing the excretory pore muscle, inhibiting the release of enzymes, metabolites, and immunomodulatory molecules. I demonstrated that the secretion of the metabolic enzyme triosephosphate isomerase (TPI) via the excretory-secretory (ESP) was unaffected by ivermectin (IVM) exposure in ML-resistant isolates. For the second objective I characterized D. immitis P-glycoprotein 11 (DimPgp-11), a gene strongly linked to the ML-resistant phenotype. I provided an extensive study on its genetic polymorphism, constitutive expression, and demonstrated, for the first time, that DimPgp-11 is strategically located surrounding the ESP in the mf lifestage. Lastly, I assessed the tryptophan catabolism enzyme, kynureninase (DimKYNU-1), a gene with newly identified genetic changes associated with ML resistance. I validated the genetic polymorphism and measured its potential impact of the constitutive expression of DimKYNU-1 and its downstream product 3-hydroxyanthranilic acid (3HA). Ultimately, the thesis provides a novel perspective on the phenotypic and genotypic implications of the development of multigenic ML resistance in D. immitis for the possible future development of anti-filarial pharmaceuticals.
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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 | 0.001 | 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".