Bacterial Pathogenesis; Infectious Disease; Microbial Pathogenesis; Microbiology
My laboratory is broadly focused on investigating microbe-microbe interactions, host-microbe interactions, and patient characteristics that influence disease severity. Our primary disease model is catheter-associated urinary tract infection (CAUTI), one of the most common healthcare-associated infections worldwide. Long-term use of indwelling catheters, which is common for management of certain conditions particularly in aging populations, results in continuous urine colonization by bacteria (bacteriuria) and can lead to infections of the bladder (cystitis), kidneys (pyelonephritis), and bloodstream (bacteremia).
My lab uses a combination of basic science and patient-oriented research, with the long-term goals of 1) identifying the uropathogen(s) most likely to cause symptomatic infection and adverse outcomes in patients, 2) utilizing an experimental model of infection to identify key virulence factors of these organisms, and 3) developing inhibitors of the identified virulence factors to reduce colonization and infection severity in vulnerable patient populations. As bacteriuria and CAUTI are frequently polymicrobial, which can influence the progression of the infection and the efficacy of antibiotic therapy, a major emphasis of this work is on understanding the contribution of polymicrobial colonization and microbe-microbe interactions to infection progression.
We recently identified the Gram-negative bacterium Proteus mirabilis as the most common cause of CAUTI in a cohort of nursing home residents, including cases of polymicrobial infection. P. mirabilis is well-known for its potent urease enzyme, which produces ammonia from the hydrolysis of urea in urine and leads to high urine pH, precipitation of polyvalent ions, and formation of urinary stones (urolithiasis). We recently determined that P. mirabilis urease activity is enhanced during co-culture with other common uropathogens in vitro and in vivo, contributing to increased tissue damage and bacteremia. Enhanced urease activity appears to be a broad phenomenon, occurring with numerous isolates of P. mirabilis during co-culture with most of the other common uropathogens, including Escherichia coli, Enterococcus faecalis, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Therefore, one project in the lab focuses on defining the underlying mechanism of enhanced urease activity and determining its potential as a therapeutic target.
Another focus of the lab is utilizing genome-wide screens to uncover new genes that contribute to pathogenesis during both monomicrobial and polymicrobial infection. We are using transposon insertion-site sequencing (Tn-Seq) to identify the full potential arsenal of P. mirabilis fitness and virulence factors during experimental CAUTI, including core factors that contribute to pathogenicity under all infection conditions tested, and accessory factors that are only required under certain infection conditions.