Integrative multi-omics reveals CUL4B as a modulator of macrophage pyroptosis and innate defense against Staphylococcus aureus.

Abstract

Staphylococcus aureus (SA) causes a broad range of invasive human diseases, increasingly complicated by antibiotic resistance. Macrophages (MΦ) play a central role in innate immunity, yet key aspects of their interaction with SA remain incompletely understood because of 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 MΦ responses 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 interleukin-1β production, consistent with altered inflammasome signaling. In a murine methicillin-resistant SA (MRSA) pneumonia model, CUL4B deficiency improved pulmonary bacterial clearance, reduced bacteremia, and decreased inflammatory tissue injury. Whole-lung and serum proteomics further revealed increased antimicrobial protein abundance and reduced markers of inflammatory damage. Together, these findings identify CUL4B as a regulator of MΦ inflammatory responses during MRSA infection and suggest a potential host-directed pathway that could be leveraged to improve outcomes against this major pathogen.