Patients undergoing cardiovascular operations are at a significant risk for nosocomial infections. Klebsiella pneumoniae is a leading cause of nosocomial infections worldwide. “Classical” K. pneumoniae, strains commonly cause multidrug-resistant (MDR) infections in compromised patients residing in hospitals and long-term care facilities. In addition, K. pneumoniae manifests as invasive, community-acquired infections caused by hypervirulent K. pneumoniae (hvKp). hvKp virulence factors are usually encoded on large non-mobile plasmids, restricting “hypervirulence” to few sequence types that are, for now, anti-microbial susceptible. Convergence of hvKp and MDR is the nightmare scenario for clinicians as these strains are highly virulent and exceptionally difficult to treat. However, we identified unique hvKp virulence plasmids containing conjugation machinery at Northwestern Memorial Hospital (NMH). Emergence of mobile-hypervirulence plasmids will inevitably cause hvKp to become more diverse and potentially MDR. In addition, we evaluated the genomes of ~2,200 MDR-Kp isolates from U.S. hospitals and identified several strains that are the result of transfer of hvKp virulence factors to MDR-cKp strains. Currently, virulence profiles and prevalence of these diverse hypervirulent isolates remain unknown. This represents a fundamental gap in our understanding of hvKp evolution and pathogenesis. Addressing this gap has potential to inform public health officials on the prevalence of these new hvKp isolates and dictate policy to prevent the spread and dissemination. I will address the central hypothesis that hvKp-like isolates are rapidly evolving and MDR-hvKp isolates are already present within the United States. This hypothesis will be tested in the following two specific aims: 1) Characterize the mechanism of pathogenesis of NMH hypervirulent K. pnuemoniae isolates. The goal of this aim is to evaluating mechanisms that confer hypervirulence of NMH strains that have the potential to transfer their hypervirulence phenotype. and 2) Characterize the plasmid content and virulence properties of MDR hvKp-like isolates collected from numerous U.S. hospitals. The goal of this aim is to determine the level of virulence and plasmid content of these MDR strains that have already acquired hvKp virulence factors via horizontal gene transfer.
|Effective start/end date||4/1/21 → 3/31/23|
- American Heart Association (837089)