Lack of Complement Factor H Contributes to Endothelial Cell Injury in Shiga Toxin Haemolytic Uraemic Syndrome
Bibliographic record
Abstract
Background: Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy that has a predilection for the kidney. In 90% of cases, HUS follows gastroenteritis secondary to infection with Shiga toxin (Stx) producing bacteria such as Escherichia coli. STEC HUS is the leading cause of acute kidney injury in children with a mortality of 5%. We have previously shown endothelial cell complement activation in a PodGb3 mouse model of STEC HUS. Here we build upon these findings to show that a reduction in glomerular endothelial CFH occurs both in our animal model and in-vitro co-culture models. Methods: To demonstrate that the podocyte Stx receptor (Gb3) is sufficient to trigger the development of HUS, we used conditional gene targeting to engineer human Gb3 expression specifically in the podocytes of mice (PodGb3). Using an in-vitro human glomerular cell co-culture model we evaluated the effects of Stx on endothelial cell injury, complement activation (C3b, C5b-9) and regulation (CD46, CD55, CFH). Results: Following intraperitoneal Stx, PodGb3 mice recapitulate all of the histopathological features of HUS. Further interrogation demonstrated glomerular endothelial cell complement activation, loss of CFH protection and rescue of the HUS phenotype following C5 inhibitor treatment. Interestingly, in co-culture studies Stx caused a reduction in glomerular endothelial CFH that was only seen in the presence of co-culture with podocytes. Conclusions: These observations provide compelling evidence for the importance of podocyte-glomerular endothelial cell cross-talk in the development of STEC HUS and suggest a possible therapeutic role for complement inhibition in patients with this devastating disease. Funding: Other NIH Support - Kidney Research UK, Academy of Medical Sciences, BMSA foundation Grant Lack of Complement Factor H contributes to endothelial cell injury in Shiga toxin Haemolytic Uraemic Syndrome (HUS): supporting Figure 1.Figure 1:: PodGB3 mice given intraperitoneal Shiga toxin show evidence of endothelial complement activation (C3b) and loss of CFH protection.Day 10 post-IP Stx glomerular immunofluorescence analysis for C3b and complemtn factor H (green) with co-staining for nephrin (red) in PodGb3 mice and controls. Scale bar, 25 μm.Fold change in corrected total glomerular fluorescence intensity (CTGF) was calculated using Image J analysis for C3b and complement factor H deposition in the glomerulus. PodGb3 n=3, controls n=3 with 30 glomeruli per mouse analysed. Unpaired T-test p value ***<0.0001.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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 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".