Granzyme A in Patients With E. Coli Bacteremic Urinary Tract Infections

Background: Survival in Granzyme A gene (gzmA) knocked-out mice was significantly longer than in wild-type mice in a murine peritonitis model (cecal ligation puncture).

Hypothesis: GZM A has a pathogenic role in sepsis in humans and gzmA polymorphisms can help to predict the risk of sepsis among patients with systemic infections (E. coli bacteremic urinary tract infections).

Objectives:

1. To assess the correlation between GZM A serum levels and systemic inflammatory response in a human model of infection/sepsis (E. coli bacteremic UTI)
2. To characterize gzmA polymorphisms among patients with E. coli bacteremic UTI
3. To determine GZM A serum kinetics among patients with E. coli bacteremic UTI
4. To characterize E. coli strains causing bacteremic UTI: antimicrobial phenotype and virulence factors ("virulome").

Methods:

• Design and setting: Prospective nested case-control study
• Study population: consecutive adult patients with bacteremic urinary tract infections (UTIs) caused by E. coli
• Exclusion criteria: Patients with conditions that significantly compromise immune status or patients exposed to urologic procedures
• Estimated sample size: 50 patients with a sepsis/ non sepsis 1:1 ratio. Septic and non septic patients will be matched on gender, age (+/- 10 years), comorbidity (Charlson score +/-1), time symptom onset to blood culture (+/- 24h)
• Measurements: GZM A serum levels will be determined on day 0, day 2-3, day 30. GZM A kinetics, gzmA polymorphisms (whole exome sequencing).Whole genome sequencing of E. coli isolates retrieved from blood cultures will be performed.
• Analysis: Association between GZM A levels and gzmA polymorphisms and sepsis will be analyzed adjusting for patient, infection and microorganism-related factors (multivariate analysis).