Identification of Clinical and Bacterial Genetic Risk Factors Associated with Klebsiella pneumoniae Infection

Klebsiella pneumoniae is a leading cause of hospital-acquired infections, including bacteremia, pneumonia, and urinary tract infections. Traditionally, this organism has been considered an opportunistic pathogen, infecting immunocompromised patients. In recent years, however, there has been development of highly antibiotic-resistant K. pneumoniae strains and the emergence of hypervirulent strains. This had led to complications in treating patients infected by K. pneumoniae and highlighted the need to understand acquisition and pathogenesis of these bacteria. Being able to identify patients at risk for infection, as well as identify potential disease-causing strains of K. pneumoniae, could aid in decreasing patient morbidity and mortality. This thesis dissertation is focused on the host and bacterial genetic risk factors that are associated with K. pneumoniae clinical infection. The central hypothesis of this work is that colonized patients are more likely to develop infection, and that specific genes in the accessory genome predict clinical infection. To test the link between colonization and infection, a cohort study of intensive care patients was performed. Among several patient risk factors identified, there was a significant and independent association between intestinal colonization and extra-intestinal infection with K. pneumoniae. To identify bacterial genetic risk factors for infection, a case-control study incorporating clinical modeling and a novel comparative genomics method called Pathogenicity-Associated Locus Sequencing (PAL-Seq) was performed. This approach identified several bacterial pathogenicity-associated loci (PALs). Combined with patient risk factors, these PALs were highly predictive of infection in our sample set. Together, these findings further our understanding of K. pneumoniae pathogenesis and have potential implications for identifying patients at risk for developing infection. Identifying colonization as a significant step in progression to infection provides an opening for potential interventions to prevent infections. Furthermore, identification of bacterial genes associated with clinical infection provides potential diagnostic targets for predicting infection in colonized patients. This work supports a paradigm for K. pneumoniae pathogenesis where colonized patients either progress to infection or remain asymptomatically colonized based on the combined effects of patient risk factors and pathogenicity associated gene loci in the accessory genome.PhDMolecular & Cellular PathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/138793/1/rmmar_1.pd