Durham, NC 27710
Pediatric infectious disease, complex infections of hospitalized children, urinary tract infections (acute, chronic, recurrent), multidrug resistant infections
We are studying human microbial ecology and the molecular basis for different bacterial infections that are of relevance to both children and adults. Summaries of the research areas are described below:
1. THE MOLECULAR BASIS FOR VIRULENCE OF UROPATHOGENIC ESCHERICHIA COLI AND URINARY TRACT INFECTIONS. Uropathogenic Escherichia coli (UPEC) is the leading cause of community-acquired urinary tract infections (UTIs). Over 100 million UTIs occur annually throughout the world including more than 10 million in U.S. adolescents and adults and result in greater than $2.5 billion in annual health care dollars. UTIs in younger children are associated with greater risk of morbidity and mortality than in older children and adults. Neonates have increased risk of urosepsis and meningitis. Febrile UTIs in children under 5 years frequently represent pyelonephritis which results in renal scarring in 27 to 64% cases in the absence of underlying urinary tract anomalies and can lead to hypertension and chronic renal failure.
Recurrent UTI causes additional morbidity. Over 25% of women with an initial UTI experience recurrent infections, and most occur within the first 6 months after the initial infection. Up to 70% of young children with UTI develop at least 1 recurrence, putting them at a higher risk for renal scarring. Most studies have shown that over 40-60% of the recurrent UPEC are the same isolate as caused the initial UTI.
A major emerging problem is that many uropathogens, bacterial causing UTI, are becoming resistant to currently available antibiotics. This is particularly true of many orally available antibiotics. Without active antibiotics to which the bacterial causing UTI are widely susceptible, clinicians are becoming increasingly limited in their ability to treat these very common infections in their clinics.
The pathogenesis of bladder infection (cystitis) in a mouse model closely mimicks human infection. UPEC adhere, invade, and amass in the superficial epithelial cells of the bladder. The biomasses of bacteria, called intracellular bacterial communities (IBC), have biofilm-like characteristics, making this a great model of in vivo biofilm formation. These first three steps in pathogenesis rely on the adhesive pilus structure called type 1 pili. After IBC formation, the bacteria disperse and flux from infected cells where they re-adhere and invade new epithelial cells. In mice, we observe that bacteria can also enter into a chronic persistent state and reemerge to produce further episodes of bacteruria months later.
Using a cutting-edge combination of microbial genetics, molecular biology, advanced microscopy, biochemistry, immunology, and animal modeling, we are exploring how UPEC interacts with the bladder epithelium to persist during acute and chronic infections. We have determined that polysialic acid capsules, present on almost all UTI-causing E. coli, and sialic acid sensing are important factors in virulence. We are elucidating novel pathways through which these factors promote a survival advantage during UTI. We are also developing novel small molecule inhibitors of capsule biogenesis as a new class of anti-infective agents. In another group of projects, we are determining the role of the FimX recombinase in epigenetic control of E. coli virulence and elucidating the role of its associated genomic island in complicated UTI and urosepsis. In a furhter project, we are using a novel combination of phage display with deep sequencing to understand the adapative immune response to human bladder infections. Last, we are investigating a hypothesis that genome stability is by itself a virulence trait and that error prone DNA replication and mismatch repair are necessary for bacterial persistence in the urinary tract.
2. ROLE OF UREAPLASMA INFECTION IN PRETERM LABOR AND PRETERM PREMATURE ONSET OF RUPTURE OF MEMBRANES
This faculty member has no reported relationships with industry.
Bateman, SL; Seed, PC. Epigenetic regulation of the nitrosative stress response and intracellular macrophage survival by extraintestinal pathogenic Escherichia coli. Molecular Microbiology. 2012;83:908-925. (2012) Abstract
Gawel, D; Seed, PC. Urinary tract infection drives genome instability in uropathogenic Escherichia coli and necessitates translesion synthesis DNA polymerase IV for virulence. Virulence. 2011;2:222-232. (2011) Abstract
LaTuga, MS; Ellis, JC; Cotton, CM; Goldberg, RN; Wynn, JL; Jackson, RB; Seed, PC. Beyond bacteria: a study of the enteric microbial consortium in extremely low birth weight infants. PLoS One. 2011;6:e27858. (2011) Abstract
Schwartz, DJ; Chen, SL; Hultgren, SJ; Seed, PC. Population dynamics and niche distribution of uropathogenic Escherichia coli during acute and chronic urinary tract infection. Infection and Immunity. 2011;79:4250-4259. (2011) Abstract
Anderson, GG; Goller, CC; Justice, S; Hultgren, SJ; Seed, PC. Polysaccharide capsule and sialic acid-mediated regulation promote biofilm-like intracellular bacterial communities during cystitis. Infection and Immunity. 2010;78:963-975. (2010) Abstract
Goller, CC; Seed, PC. High-throughput identification of chemical inhibitors of E. coli Group 2 capsule biogenesis as anti-virulence agents. PLoS One. 2010;5:e11642. (2010) Abstract
Cegelski, L; Pinkner, JS; Hammer, ND; Cusumano, CK; Hung, CS; Chorell, E; Aberg, V; Walker, JN; Seed, PC; Almqvist, F; Chapman, MR; Hultgren, SJ. Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation. Nature Chemical Biology. 2009;5:913-919. (2009) Abstract
Hannan, TJ; Mysorekar, IU; Chen, SL; Walker, JN; Jones, JM; Pinkner, JS; Hultgren, SJ; Seed, PC. LeuX tRNA-dependent and -independent mechanisms of Escherichia coli pathogenesis in acute cystitis. Molecular Microbiology. 2008;67:116-128. (2008) Abstract
Wright, KJ; Seed, PC; Hultgren, SJ. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili. Cellular Microbiology. 2007;9:2230-2241. (2007) Abstract
Justice, SS; Hunstad, DA; Seed, PC; Hultgren, SJ. Filamentation by Escherichia coli subverts innate defenses during urinary tract infection. Proceedings of the National Academy of Sciences of USA. 2006;103:19884-19889. (2006) Abstract
Pinkner, JS; Remaut, H; Buelens, F; Miller, E; Aberg, V; Pemberton, N; Hedenström, M; Larsson, A; Seed, P; Waksman, G; Hultgren, SJ; Almqvist, F. Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria. Proceedings of the National Academy of Sciences of USA. 2006;103:17897-17902. (2006) Abstract