Iron acquisition in the adult filarial nematode «Brugia malayi» and the effect of ivermectin on heme binding proteins and the transcriptome
Bibliographic record
Abstract
Human filarial nematode infections caused by Wucheria bancrofti, Brugia malayi and Brugia timori can lead to lymphatic filariasis (LF), and those due to Onchocerca volvulus can lead to onchocerciasis or river blindness, affecting millions of people in tropical and sub-tropical regions. Brugia malayi has been an excellent model to study human filarial diseases, in particular by employing culture systems, the impact of which on the parasites is unknown. One of our objectives was to evaluate changes in gene expression due to in vitro cultivation of Brugia malayi, as an index of adaptation to removal from the host. We examined the global transcriptome of this parasite by Illumina sequencing technology from the time the parasites were extracted from jirds in Georgia (USA), shipped to Montreal (Canada), and after maintenance for up to 5 days in culture. It was important to assess the effects of culture on the parasite prior to measuring the effects of exposure to drugs such as ivermectin. Ivermectin is the drug of choice for mass drug administration for the control and elimination of onchocerciasis, and for lymphatic filariasis in areas where the diseases are co-endemic. Ivermectin exposure in vivo results in an initial dramatic drop in the levels of circulating or dermal microfilariae, followed by long-term suppression of reproduction. The mechanisms involved in this long-term sterilization are not understood. The main objective of my work was to study the in vitro effects of ivermectin on adult female B. malayi at the proteomic and transcriptome levels using LC/MS/MS and Illumina Sequencing technology. We hypothesized that ivermectin causes paralysis of pharyngeal pumping in these parasites, an effect that would prevent worms from acquiring essential nutrients such as iron-containing proteins (i.e., transferrin). Iron deprivation would have down-stream effects on the biosynthesis of heme by the symbiotic Wolbachia bacteria, which is crucial for reproduction and ATP synthesis as well as other important biological functions. This work led to the identification of genes and heme-binding proteins involved in reproduction and in particular meiosis, which were dysregulated in worms exposed to ivermectin compared to untreated worms. We also established that an iron transporter is expressed in the intestine of B. malayi and showed that this Divalent Metal Transporter 1 (DMT1) can function as an iron transporter in an iron-transport deficient strain of yeast, Saccharomyces cerevisiae. That this transporter is expressed in the intestine of filariid nematodes suggests that the gut is functional and supports the hypothesis that the long-term effects of ivermectin on filarial reproduction could be explained, at least in part, by iron deprivation due to paralysis of pharyngeal pumping.
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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".