The Impact Of Propofol On Klebsiella Lung Infection
thesisposted on 08.02.2018, 00:00 authored by David Richard Mains
Klebsiella pneumoniae is a Gram negative facultative anaerobic bacterium commonly found in environmental reservoirs and is capable of colonizing human niches. In neonates, the elderly, and generally immunodeficient persons, K. pneumoniae is capable of causing invasive disease. This is of clinical significance due to the general distress caused by a variety of procedures in the healthcare setting that can increase the risk of infection. As a direct result, K. pneumoniae is the cause of approximately 12,000 healthcare-associated infections every year in the United States. The anesthetic propofol is frequently utilized in the clinic for sedation and previous work in the Freitag lab has demonstrated that brief sedation with propofol is sufficient to dysregulate immune responses to bacterial bloodstream infections, leading to more severe pathology and impaired resolution. Herein, we investigated whether propofol sedation would lead to altered immune responses in a K. pneumoniae lung infection model. Propofol was found to increase lung burdens at early time points compared to controls, while simultaneously increasing immune cell recruitment to the lungs, suggesting that these responding populations were functionally deficient. Furthermore, propofol sedation also led to increased lung tissue destruction with K. pneumoniae establishing large replicative niches. Gene expression analysis in the lung revealed that propofol was precipitating a hyper-inflammatory response in the lung that preceded a systemic inflammatory response comparable to clinical sepsis. In light of these findings, we investigated whether propofol sedation would have any impact on Klebsiella virulence factor requirements in the lung using high-throughput insertion sequencing. We identified multiple gene products that were differentially required for successful lung outgrowth depending on the sedative used during infection, demonstrating that propofol sedation affects both the host immune response and Klebsiella’s required virulence repertoire during lung infection.