Fibrinogen γ′ promotes host survival during Staphylococcus aureus septicemia in mice
Bibliographic record
Abstract
BackgroundStaphylococcus aureus is a common gram-positive bacterium that is the causative agent for several human diseases, including sepsis. A key virulence mechanism is pathogen binding to host fibrinogen through the C-terminal region of the γ-chain. Previous work demonstrated that FggΔ5 mice expressing mutant fibrinogen γΔ5 lacking a S. aureus binding motif had significantly improved survival following S. aureus septicemia. Fibrinogen γ′ is a human splice variant that represents about 10% to 15% of the total fibrinogen in plasma and circulates as a fibrinogen γ′-γ heterodimer (phFibγ′-γ). The fibrinogen γ′-chain is also expected to lack S. aureus binding function.ObjectiveDetermine if human fibrinogen γ′-γ confers host protection during S. aureus septicemia.MethodsAnalyses of survival and the host response following S. aureus septicemia challenge in FggΔ5 mice and mice reconstituted with purified phFibγ′-γ or phFibγ-γ.ResultsReconstitution of fibrinogen-deficient or wildtype mice with purified phFibγ′-γ prior to infection provided a significant prolongation in host survival relative to mice reconstituted with purified phFibγ-γ, which was superior to that observed with heterozygous FggΔ5 mice. Improved survival could not be accounted for by quantitative differences in fibrinogen-dependent adhesion or clumping, but phFibγ′-γ-containing mixtures generated notably smaller bacterial aggregates. Importantly, administration of phFibγ′-γ after infection also provided a therapeutic benefit by prolonging host survival relative to administration of phFibγ-γ.ConclusionThese findings provide the proof-of-concept that changing the ratio of naturally occurring fibrinogen variants in blood could offer significant therapeutic potential against bacterial infection and potentially other diseases.
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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 | 0.000 | 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) | 0.000 | 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".