Myeloid Cell-specific Ablation of Caspase 8 Improves Outcomes in Influenza A-induced Acute Respiratory Distress Syndrome

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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