A40 THE ROLE OF HYPOXIA-INDUCIBLE FACTOR IN CELLULAR METABOLIC ADAPTATION UPON <i>GIARDIA</i> INFECTION
Bibliographic record
Abstract
Abstract Background Recent findings have highlighted the integral role of oxygen tension in gastrointestinal (GI) homeostasis. During hypoxia when oxygen supply is limited, mammalian cells utilize the Hypoxia-Inducible Factor (HIF) complex to activate genes that promote cell survival and alter glucose metabolism. The GI system exists in a state of physiologic hypoxia, subject to further alterations by pathogens. Although tissue and blood parasites are known to influence tissue oxygen tension, little is known regarding the modulation of hypoxia and HIF by enteric parasites. Aims This project aims to characterize the effect of Giardia duodenalis, a common enteric protozoan that perturbs gastrointestinal function leading to diarrheal disease, on the cellular hypoxic response. We hypothesize that hypoxia-associated genes are activated upon Giardia infection, leading to an adaptive metabolic response with increased glycolytic flux to maintain cellular bioenergetic homeostasis. Methods Caco-2 colonic epithelial cells were infected with Giardia isolate GS/M (MOI 10) for 1.5 or 4.5 hours to capture early and peak HIF activation, under normoxic (21% O2) or hypoxic (1%O2, STEMCELL hypoxia incubator) conditions. RNA was extracted for RT-qPCR to assess transcriptional changes of known HIF-target genes. Intracellular metabolite analysis via liquid-chromatography mass-spectrometry (hydrophilic-interaction chromatography method) was performed to assess HIF-mediated metabolic changes in uninfected and Giardia-infected cells (MOI 10) exposed to the hypoxia mimetic DMOG or the HIF inhibitor PX-478. Results Under normoxic conditions, genes associated with compensatory cellular stress responses such as VEGFA, ANKRD37, GADD45A, and glycolysis-associated genes HK2, and LDHA are upregulated in Giardia-infected cells in a time-dependent manner (pampersand:003C0.05). Under hypoxic conditions, fewer HIF-target genes are upregulated (e.g., VEGFA, GADD45A, PGK1; pampersand:003C0.05), suggesting Giardia-infected cells behave similarly to uninfected cells with constant HIF activation. Analysis of the Caco-2 intracellular metabolome indicates HIF-dependent changes in amino acid (e.g., glycine, threonine) and nucleic acid (e.g., guanosine, inosine, uracil) metabolism. DMOG treatment altered the production of glycolytic intermediates (e.g., DHAP, PEP), confirming the promotion of glycolytic flux by HIF. Conclusions Both cell-stress-related and glucose-metabolism HIF target genes are activated upon Giardia infection. As well, some metabolic changes are dependent on HIF activation. These novel findings indicate Giardia promotes a hypoxic state in human intestinal cells, highlighting a metabolic cell rescue mechanism in response to enteropathogens. Furthermore, understanding the role of hypoxia in enteric parasitic infections will shed light on the potential of HIF as a therapeutic target. Funding Agencies Natural Sciences and Engineering Research Council of Canada (NSERC)
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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".