Integrative Multi-omics Reveals CUL4B as a modulator of Macrophage Pyroptosis and Innate Defense to Staphylococcus aureus

Macrophages (MΦ) play central roles in innate immunity, yet key aspects of their interaction with SA remain incompletely understood due to the pathogen’s diverse immune evasion strategies. Using multi-omics and systems-level analytics, we identified the E3 ubiquitin ligase Cullin 4B (CUL4B) as a host factor that modulates MΦresponses to SA infection.

CRISPR-mediated deletion of CUL4B in human THP-1 MΦ enhanced intracellular bacterial killing, reduced cell death, decreased caspase-1 activation, and lowered IL-1β production, consistent with altered inflammasome signaling. In a murine MRSA pneumonia model, CUL4B deficiency improved pulmonary bacterial clearance, limited systemic dissemination, and decreased inflammatory tissue injury. Whole-lung and serum proteomics further revealed increased antimicrobial protein abundance and reduced markers of inflammatory damage.