FBXO11 governs macrophage cell death and inflammation in response to bacterial toxins

Area of Science:

• Immunology
• Molecular Biology
• Microbiology

Background:

• Staphylococcus aureus infections, including pneumonia and sepsis, are often driven by the Panton-Valentine leukocidin (PVL) toxin.
• PVL induces myeloid cell death and inflammation by targeting the complement 5a receptor 1 (C5aR1).
• Mechanisms regulating C5aR1 expression and PVL activity are not fully understood.

Purpose of the Study:

• To identify host factors modulating PVL toxicity.
• To elucidate the role of F-box protein 11 (FBXO11) in PVL-mediated pathogenesis.
• To investigate FBXO11's impact on C5aR1 expression and inflammatory responses.

Main Methods:

• Genome-wide CRISPR/Cas9 screening in macrophages.
• Genetic deletion and ectopic expression of FBXO11.
• Analysis of C5aR1 mRNA and protein levels.
• Assessment of IL-1β secretion following NLRP3 activation.
• Evaluation of PVL-mediated cytotoxicity.

Main Results:

• FBXO11 was identified as a key promoter of PVL toxicity.
• FBXO11 deletion reduced C5aR1 mRNA expression, decreasing PVL sensitivity.
• Restoration of C5aR1 expression or LPS priming rescued PVL toxicity in FBXO11-deficient cells.
• FBXO11 also suppressed IL-1β secretion in response to bacterial toxins via BCL-6-dependent and -independent pathways.

Conclusions:

• FBXO11 is a critical regulator of C5aR1 expression, thereby controlling macrophage susceptibility to PVL.
• FBXO11 influences both PVL-induced cell death and inflammatory cytokine production.
• Targeting FBXO11 may offer a novel therapeutic strategy against severe Staphylococcus aureus infections.