Uncovering a new family of conserved virulence factors that promote the production of host-damaging outer membrane vesicles in gram-negative bacteria.

Summary

A conserved SDR family (CprA/HlyF orthologs) drives outer membrane vesicle production that blocks autophagy and enhances non-canonical inflammasome activation, increasing Gram-negative virulence. Deletion of cprA reduces virulence in a murine sepsis model, highlighting anti-virulence targets.

Key Findings

• CprA expression induces OMVs that block autophagic flux and enhance non-canonical inflammasome activation.
• P. aeruginosa lacking cprA shows reduced virulence in a murine sepsis model.
• SDR orthologs in E. coli (HlyF), Y. pestis, and R. solanacearum similarly promote OMV production and autophagy blockade.

Clinical Implications

Targeting SDR-driven OMV biogenesis or restoring autophagic flux may attenuate Gram-negative virulence without exerting antibiotic pressure.

Limitations

• Quantitative contribution of OMV-mediated effects to overall virulence across diverse clinical isolates remains to be defined
• Translational relevance to human infection and therapeutic targeting needs in vivo pharmacologic validation

Future Directions

Develop small-molecule or biologic inhibitors of SDR-driven OMV biogenesis; test host-directed strategies to restore autophagy and blunt inflammasome activation in sepsis models.