TThis study hypothesizes that the gallbladder (GB) is the critical site of Pseudomonas aeruginosa (PA) amplification following systemic infection leading directly to transmission through intestinal shed. Specific Aims: (1) Identify and validate novel genes and pathways critical for PA expansion in the gallbladder (2) Explore the role of the gallbladder in infection outcomes and examine the impact of antibiotic treatment on fecal excretion of PA following bloodstream infection. Study Design: Through utilization of transposon insertion sequencing and RNA-sequencing technologies, we will define the genes and pathways essential for survival in the gallbladder. Candidate genes will be deleted and strains re-examined for virulence, gallbladder replication, intestinal shed, and transmissibility. Mice with their gallbladders removed (cholecystectomized) will be challenged intravenously with PA and infection survival will be measured. Next, infected mice will be challenged with a variety of clinically relevant antibiotics and assess the impact on infection dynamics, fecal excretion and transmission. Cancer Relevance: Insights into the mechanisms by which PA disseminates during bacteremia, a description of pathways critical for bacterial replication in protected niches such as the GB, and a deeper understanding of how antibiotic treatment impacts environmental contamination by PA following invasive infection will be critical for 1) developing novel therapeutic agents important for treating PA infections and minimizing environmental contamination and 2) modifying current infection control practices to prevent transmission of PA in immunocompromised patients. Development of such agents could improve both clinical outcomes and survival in cancer patients.
|Effective start/end date||9/1/20 → 8/31/24|
- American Cancer Society (134251-CSDG-20-053-01-MPC)