Myeloid Cell-specific Ablation of Caspase 8 Improves Outcomes in Influenza A-induced Acute Respiratory Distress Syndrome
Bibliographic record
Abstract
Abstract RATIONALE: Influenza A (IAV) has caused many of the largest pandemics in human history and continues to be a global health concern, infecting up to 20% of the global population in a flu season with 3-5 million cases resulting in severe illness and up to 650000 resulting in death. Severe IAV infection can lead to acute respiratory distress syndrome (ARDS), where edematous fluid infiltration and diffuse alveolar damage may progress to multiple organ dysfunction syndrome (MODS) with up to a 60% mortality rate. Constant changes in the IAV genome challenges IAV-specific drug development; thus, interventions against IAV infection are an ongoing need in critical care. Myeloid cells are key facilitators of the immune response to IAV but their overactivity is associated with poorer outcomes in severe IAV infection—a nuanced regulation of myeloid cell death is required for disease resolution. Caspase 8 acts at the intersection of many myeloid cell death pathways and is overexpressed in IAV-infected myeloid cells of both murine and human origin; myeloid cell caspase 8 may be a valuable therapeutic target in IAV-induced ARDS. METHODS: Myeloid cell-specific caspase 8 knockout mice were generated by crossing caspase 8 exon 3-flanking LoxP (Casp8fl/fl) mice with LysM cre (LysMcre/cre) mice. Myeloid cell-specific caspase 8 knockout (KO) mice were of the genotype Casp8fl/fl LysMcre/cre and compared with littermate wild type control (WT) mice of the genotype Casp8fl/fl. KO and WT mice were infected intranasally with influenza A/Puerto Rico/8/1934 (H1N1) at 107 TCID50. 10-day survival was assessed. Caspase 8 was measured in myeloid cells, whole lung lysates, and whole kidney lysates by Western blot and qRT-PCR; viral gene expression was measured in post-mortem whole lung lysates by qRT-PCR. RESULTS: Confirmation of the myeloid cell-specific knockout of caspase 8 was indicated by significantly reduced levels of caspase 8 in KO versus WT myeloid cells at both the RNA and protein levels while KO versus WT whole lung and kidney lysates showed no significant differences. KO mice demonstrated a significant improvement in 10-day survival compared to WT. Whole lung lysates of KO mice had significantly reduced expression of the viral genes hemagglutinin, neuraminidase, nucleoprotein, matrix protein, and polymerase basic 1. CONCLUSION: The absence of caspase 8 in myeloid cells improves outcomes in IAV-induced ARDS in a preclinical murine model. Myeloid cell-targeted modulation of caspase 8 may provide a novel therapeutic strategy for severe IAV infection and ARDS.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".