K. pneumoniae is a common cause of hospital-acquired infections, including urinary tract infections, bloodstream infections, and pneumonia. These infections are increasingly difficult to treat due to antibiotic resistance. Recently, strains of K. pneumoniae have emerged in the United States and throughout the world that are resistant to carbapenems, antibiotics of last resort against severe gram-negative infections. Carbapenem resistant K. pneumoniae and other related bacteria are collectively termed Carbapenem Resistant Enterobacteriaceae (CRE). CDC Director Thomas Frieden has termed CRE "nightmare bacteria" because of high mortality from untreatable infections.
Host and Klebsiella pneumoniae factors associated with clinical infection
K. pneumoniae is a common colonizer of hospitalized patients, but little is known about how it progress to cause infections. Whole genome sequencing indicates that a significant portion of the genome varies between isolates, and these variable regions contain potential virulence genes. To identify genes required for invasion in colonized patients, we are performing comparative genomics between colonizing and invasive isolates.
The Host Response to Microbial Iron Metabolism
K. pneumoniae and other gram-negative pathogens secrete molecules called siderophores to scavenge iron that is required for bacterial replication. These siderophores are some of the strongest iron chelators and can strip iron from host proteins and deplete intracelluar iron in human cells. To disrupt bacterial iron acquisition, mucosal epithelial cells and neutrophils secrete the protein Lipocalin 2 that specifically binds the K. pneumoniae siderophore enterobactin. Binding of enterobactin by lipocalin can starve K. pneumoniae of iron. However virulent isolates of K. pneumoniae may secrete additional siderophores that Lipocalin 2 cannot bind and are able to acquire iron despite Lipocalin 2. However, the combination of enterobactin and Lipocalin 2 can trigger pro-inflammatory cytokine secretion from epithelial cells. In this way, host cells may use inflammation as a back-up mechanism when the ability of Lipocalin 2 to disrupt bacterial iron acquisition is overwhelmed. We are interested in pathologic effects of siderophore-mediated iron chelation on host cells and the inflammatory effects of siderophores and Lipocalin 2 during infection.
Klebsiella pneumoniae virulence factors required for lung infection and invasion
Despite its high incidence as a cause of hospital-acquired infection, few virulence factors have been identified in K. pneumoniae. Discovery of factors that are required for survival and replication in the host could facilitate development of new therapeutics. To identify novel fitness factors required during infection, we perform genetic screens using random mutagenesis and high throughput sequencing to map and count mutants that are defective for growth in animal models (InSeq).