# Deciphering the impact of sedative choice on the dynamics of Klebsiella pneumoniae lung infection

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $197,895

## Abstract

Summary
Healthcare-associated infections adversely impact patient outcomes and increase healthcare costs by billions
of dollars each year. Anesthetic administration is associated with a significantly increased risk of infection via
its alterations of immune signaling and immune effector cell function. Despite the increasing recognition that
anesthetics modulate immunity, relatively little remains known regarding the breadth of mechanisms by which
drugs that target the nervous system influence host immune responses. We have previously demonstrated that
brief sedation with propofol, the most commonly used drug for anesthetic induction, dramatically increases host
susceptibility to microbial infection. Propofol is widely used for patients requiring intubation and mechanical
ventilation, and patients in the ICU can remain sedated with propofol for days. To better define the impact of
propofol sedation on respiratory disease, we have developed a mouse model of lung infection using the Gram-
negative opportunistic pathogen Klebsiella pneumoniae (Kp). Kp is a growing threat worldwide as a
nosocomial pathogen due to its rapid acquisition of antimicrobial resistance; in addition, hypervirulent strains
causing community-acquired infections have been recently reported. Preliminary experiments indicate that
propofol sedation dramatically increases the severity of Kp disease pathology within the lungs and promotes
bacterial dissemination to distal tissues. Using transposon insertion sequencing (INSeq) and libraries of Kp
insertion mutants, we have further demonstrated that the choice of sedative influences the selection of Kp
mutants that are defective for growth within the infected lung. These results strongly suggest that propofol not
only influences the pathology and outcome of lung infection, but that it also differentially impacts the arsenal of
bacterial virulence factors required for disease. This proposal is thus designed to explore two related and
mutually important hypotheses, those being (1) that propofol increases host susceptibility to microbial (Kp)
infection in the lung via alterations in immune signaling that interfere with the recruitment and function of innate
immune effector cells; and (2) the choice of sedation alters the lung environment in ways that impact the Kp
global virulence repertoire required for bacterial growth in tissues. Aim 1 experiments will determine how
sedation choice influences the outcome and progression of Kp lung infection in vivo. Aim 2 will functionally
characterize Kp mutants identified based on their virulence being differentially impacted by sedation with
propofol versus ketamine/xylazine. Overall, these experiments will provide valuable and important information
regarding the impact of sedation on respiratory infection outcome and prognosis.

## Key facts

- **NIH application ID:** 10527379
- **Project number:** 5R21AI166098-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Nancy Elizabeth Freitag
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $197,895
- **Award type:** 5
- **Project period:** 2021-11-16 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527379

## Citation

> US National Institutes of Health, RePORTER application 10527379, Deciphering the impact of sedative choice on the dynamics of Klebsiella pneumoniae lung infection (5R21AI166098-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10527379. Licensed CC0.

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