A271 THE HELICOBACTER PYLORI VACA TOXIN IMPAIRS LYSOSOMAL CALCIUM CHANNEL TRPML1 ACTIVITY TO PROMOTE COLONIZATION
Bibliographic record
Abstract
Helicobacter pylori (H. pylori) is a proven carcinogen for gastric cancer. The vacuolating cytotoxin A (VacA) is a bacterial virulence factor that promotes more severe disease and gastric colonization. VacA generates a unique reservoir for H. pylori within gastric cells conferring bacterial survival advantage. Normally the lysosome and autophagy pathways target and eliminate intracellular pathogens. VacA disrupts the endolysosomal pathway to form large intracellular vacuoles and impairs host-cell autophagy to generate the intracellular niche. However, the mechanism by which VacA alters the endolysosomal pathway is unknown. Proper vesicular trafficking, lysosomal biogenesis and autophagy pathway require a functional Mucolipin Transient Receptor Membrane Calcium channel 1 (TRPML1). Interestingly, TRPML1 deficient cells display enlarged vacuoles and disrupted autophagy, as observed in VacA-treated cells. Furthermore, TRPML1 deficient mice display hypergastrinemia and hypochlorhydria, conditions observed during H. pylori infections. Hypothesis: We hypothesized that VacA inhibits TRPML1 to promote an intracellular niche. We employed gastric cells, murine wild type and trpml1 -/- and human organoid models as well as in vivo murine infection in wild type and trpml1 -/- mice using VacA+ and isogenic VacA mutant H. pylori. We found elevated intraluminal lysosomal calcium levels in VacA-treated gastric adenocarcinoma (AGS) cells consistent with disrupted TRPML1 activity. Furthermore, using a small molecule agonist to activate TRPML1 in VacA+H. pylori-infected human gastric cell lines and organoids restores normal lysosomal and autophagic function, eliminating the intracellular protective niche and resulting in efficient bacterial killing. Consistent with these observations, we found that VacA+ H. pylori infected mice displayed intracellular bacteria in parietal cells. Similarly, the enlarged lysosomal-like vacuoles present in the parietal cells of trpml1-null mice were colonized by mutant VacA-H. pylori. Altogether, we identify TRPML1 as a target that VacA exploits to evade host killing. We provide initial evidence that TRPML1 could serve as the first non-bacterial target to kill intracellular H. pylori. In this era of increasing antibiotic resistance and urgent need for research and development of new antimicrobials, we expect that TRPML1 agonists could be explored as novel therapies against intracellular pathogens. CAG, CIHR
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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 | 0.001 | 0.001 |
| 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".