Integrative multi-omics reveals CUL4B as a modulator of macrophage pyroptosis and innate defense against 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.
Authors
- Pengbo Zhou (ORCID: https://orcid.org/0000-0002-4912-2901)
- Gustav Vaaje‐Kolstad (ORCID: https://orcid.org/0000-0002-3077-8003)
- Angela Meier (ORCID: https://orcid.org/0000-0002-6766-531X)
- Helen O. Masson (ORCID: https://orcid.org/0000-0002-1311-1063)
- George Sakoulas (ORCID: https://orcid.org/0000-0002-6063-6217)
- Ingrid Cornax (ORCID: https://orcid.org/0009-0004-3688-9056)
- Jasmine Tat (ORCID: https://orcid.org/0009-0009-5969-7416)
- Ka Pui Sharon Yau (ORCID: https://orcid.org/0000-0002-4250-5635)
- James T. Sorrentino (ORCID: https://orcid.org/0000-0002-7058-9987)
- Tom Eirik Mollnes (ORCID: https://orcid.org/0000-0002-5785-802X)
- Fatemeh Askarian (ORCID: https://orcid.org/0000-0002-7438-4671)
- Mona Johannessen (ORCID: https://orcid.org/0000-0003-4604-8600)
- Consuelo Sauceda (ORCID: https://orcid.org/0000-0002-1487-6631)
- Alexandria Hoffman (ORCID: https://orcid.org/0000-0002-8208-8995)
- Armin Kousha (ORCID: https://orcid.org/0009-0003-0461-9951)
- Victor Nizet (ORCID: https://orcid.org/0000-0003-3847-0422)
- Kristin Pettersen (ORCID: https://orcid.org/0009-0006-0262-5372)
- Nathan E. Lewis (ORCID: https://orcid.org/0000-0001-7700-3654)
- Hunter Gage
- Jonathan M. Monk (ORCID: https://orcid.org/0000-0002-3895-8949)
- Daniel Sun (ORCID: https://orcid.org/0000-0001-7119-6045)
- David J. Gonzalez (ORCID: https://orcid.org/0000-0003-1423-5970)
- Chih‐Ming Tsai (ORCID: https://orcid.org/0000-0001-7305-7401)
- Natalie Chavarria (ORCID: https://orcid.org/0009-0007-0581-9620)
- Ella McLaren (ORCID: https://orcid.org/0000-0002-9830-033X)
- Yu Yan (ORCID: https://orcid.org/0009-0008-7968-7904)
- Siri Yendluri
- Jacob Wozniak
- Stanley Davis (ORCID: https://orcid.org/0009-0007-0650-7522)
Institutions
- Oslo University Hospital (NO)
- University of Georgia (US)
- University of Oslo (NO)
- Cornell University (US)
- Nordland Hospital Trust (NO)
- University of California San Diego (US)
- Nordland Hospital (NO)
- 657 Oslo (NO)
- Norwegian University of Life Sciences (NO)
- Washington State University (US)
- UiT The Arctic University of Norway (NO)
Publication Details
- Journal
- Science Advances
- Published
- 2026-10-14
- DOI
- https://doi.org/10.1126/sciadv.aeh4023
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases