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Research Interests

 

Integrated modeling of Klebsiella infection risk in colonized patients

Klebsiella pneumoniae members of the species complex are a leading cause of hospital-acquired infections in the United States and the most common Carbapenem-resistant Enterobacteriaceae (CRE) and Extended-Spectrum Beta-lactamase (ESBL) species. Infections with CRE cause up to 50% mortality from sepsis, and both ESBL and CRE infections are a significant cause of excess morbidity and hospital costs. Patients with Klebsiella gastrointestinal colonization are at a high risk of subsequent disease and become infected with their colonizing strain.

Testing for colonization could provide an ideal opportunity for infection prevention interventions, but how the complex interaction of patient and bacterial factors determines infection risk is unclear. To close this gap in knowledge, we have assembled a multi-disciplinary team of physician-scientists, epidemiologists, bioinformaticians, and statisticians with expertise in clinical microbiology, microbial pathogenesis and infectious diseases.

The objective of this project is to identify the bacterial and host factors that predict K. pneumoniae infections in colonized patients. Our central hypothesis is that K. pneumoniae strains vary in their virulence potential, and the combination of K. pneumoniae genotype and host susceptibility determines the risk of disease in a colonized patient. Combining a multi-site clinical study with clinical modeling, comparative genomics, and experimental models, we are identifying and characterizing Klebsiella genes that increase infection risk in colonized patients. In parallel, we are identifying patient risk factors for infection and developing integrated models that account for both host susceptibility and bacterial genetics in predicting infection risk. We seek to translate these findings into prognostic tests that can identify high-risk patients who could benefit most from interventions to prevent Klebsiella infections.

 

Fitness of gram-negative pathogens during bacteremia

We are losing the battle against antibiotic-resistant Gram-negative bacterial pathogens in our hospitals and clinical care facilities. The CDC estimates that over 2 million people are infected annually with 17 species of antibiotic-resistant bacterial pathogens, killing 23,000 people per year. Over half of the species are Gram-negative pathogens including carbapenem-resistant Enterobacteriaceae (CRE) and the non-fermenting opportunistic pathogen Acinetobacter baumannii. Thus, there is an urgent need to identify unique (species-specific) and common (required by most of the six Gram-negative species) fitness and virulence factors required by these species for bacteremia, and map key metabolic pathways and essential gene sets used by these pathogens in vivo. Our long-term goal is to delineate the mechanisms of pathogenesis in Gram-negative bacteria that cause hospital-acquired infections.

Our central hypothesis is that based on the relatedness of species at the family (Enterobacterales) and class (A. baumannii) levels, these Gram-negative pathogens require a combination of orthologous core functions and species-specific fitness factors to acquire nutrients and evade host responses during bacteremia. In a multi-institute collaboration, we are identifying genes that are required for bacteremia through transposon-insertion sequencing (Tn-Seq), genes that are preferred or repressed through transcriptional analysis (RNA-Seq), and those that impact in vivo replication rates. Combining these experimental findings with comparative genomics across species, we are identifying conserved genes and pathways that may serve as novel therapeutic targets to treat Gram-negative bacteremia.