Tissue compartmentalization enables Salmonella persistence during chemotherapy

Area of Science:

• Infectious Diseases
• Immunology
• Microbiology

Background:

• Antimicrobial chemotherapy can fail to eradicate pathogens, leading to relapsing diseases.
• In vitro studies suggest antibiotic persistence mechanisms, but in vivo relevance is unclear.
• Studying scarce pathogen survivors in host tissues is challenging.

Purpose of the Study:

• To investigate the in vivo relevance of antibiotic persistence mechanisms.
• To localize and characterize rare surviving Salmonella in mouse spleen.
• To understand the causes of antimicrobial chemotherapy failure.

Main Methods:

• High-resolution whole-organ tomography to study Salmonella in mouse spleen.
• Analysis of Salmonella survival, replication, and host immune cell interactions.
• Evaluation of chemotherapy efficacy and adjunctive therapy effects.

Main Results:

• Chemotherapy cleared >99.5% of Salmonella, but a subset persisted in the spleen's white pulp.
• Antimicrobial clearance required support from neutrophils and monocytes, which were less dense in the white pulp.
• Declining neutrophil densities during treatment led to insufficient Salmonella clearance and treatment failure.
• Adjunctive therapies sustaining inflammatory support enabled effective Salmonella clearance.

Conclusions:

• Uneven Salmonella tissue colonization and spatiotemporal inflammation dynamics cause pathogen persistence.
• Host immune cell dynamics, not just drug exposure or pathogen tolerance, are critical for antimicrobial clearance.
• A powerful approach was established to investigate scarce pathogen subsets in complex host environments.