Patrick C. Seed, MD, PhD

Department / Division:
Pediatrics / Infectious Diseases

Address:
DUMC 3499
Durham, NC 27710

Appointment Telephone:
919-668-4000

Office Telephone:
919-684-9590

Fax Telephone:
919-681-2089

• MD, University of Rochester School of Medicine and Dentistry (New York), 1998

• Pediatrics, University of Michigan, 1998-2002

• Pediatric Infectious Diseases, Washington University (Missouri), 2002-2005

• PhD, Microbiology and Immunology, University of Rochester (New York), 1998

Clinical Interests:
Pediatric infectious disease, complex infections of hospitalized children, urinary tract infections (acute, chronic, and recurrent)

Research Interests:
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 7 million in U.S. adolescents and adults and result in billions of 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 sa me isolate as caused the initial UTI.

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 molecular 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.  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.  In collaboration with Dr. Amy Murtha in Obstetrics and Gynecology, we have found that Ureaplasma sp. and Mycoplasma sp. are associated with the site of rupture during PPROM.  We are now elucidating the mechanisms of adherence of Ureaplasma parvum with the amniotic membranes and studying the host response to this interaction.

3. DEVELOPMENT OF THE GUT MICROBIOME IN EXTREMELY LOW BIRTH WEIGHT INFANTS.  Extremely low birth weight babies (<1000 g at birth) have serious risks of morbidity and mortality.  Many of medical issues originate from the gut including sepsis, necrotizing enterocolitis, and nutritional failure.  We are determining the constituency and succession of the gut microbiome in these infants and elucidating how breast milk feeding modifies its development.  This project utilizes a range of cutting edge molecular techniques including whole genome amplification, PCR, next generation amplicon sequencing, shotgut metagenomics, and advanced bioinformatics/genomics.

Representative Publications:
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.  Mol Microbiol.  2008 Jan;67(1):116-28. (2008) Abstract

Wright KJ, Seed PC, Hultgren SJ. Development of intracellular bacterial communities of uropathogenic Escherichia coli depends on type 1 pili.  Cell Microbiol.  2007 Sep;9(9):2230-41. (2007) Abstract

Uhlmann EJ, Seed PC, Schwan TG, Storch GA. Tick-borne relapsing fever polymerase chain reaction of tick-borne relapsing fever caused by Borrelia hermsii.  Pediatr Infect Dis J.  2007 Mar;26(3):267-9. (2007) Abstract

Lenfestey RW, Smith PB, Moody MA, Clark RH, Cotten CM, Seed PC, Benjamin DK Jr. Predictive value of cerebrospinal fluid parameters in neonates with intraventricular drainage devices.  J Neurosurg.  2007 Sep;107(3 Suppl):209-12. (2007) 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. Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17897-902. (2006) Abstract

Justice SS, Hunstad DA, Seed PC, Hultgren SJ. Filamentation by Escherichia coli subverts innate defenses during urinary tract infection.  Proc Natl Acad Sci U S A.  2006 Dec 26;103(52):19884-9. (2006) Abstract

Elward A, Grim A, Schroeder P, Kieffer P, Sellenriek P, Ferrett R, Adams HC, Phillips V, Bartow R, Mays D, Lawrence S, Seed P, Holzmann-Pazgal G, Polish L, Leet T, Fraser V. Outbreak of Salmonella javiana infection at a children's hospital. Infect Control Hosp Epidemiol. 2006 Jun;27(6):586-92. (2006) Abstract

Wright KJ, Seed PC, Hultgren SJ. Uropathogenic Escherichia coli flagella aid in efficient urinary tract colonization. Infect Immun. 2005 Nov;73(11):7657-68. (2005) Abstract

Seed PC, Hultgren SJ. Blueprinting the regulatory response of Escherichia coli to the urinary tract. Trends Microbiol. 2005 Jun;13(6):246-8. (2005) Abstract

de Kievit T, Seed PC, Nezezon J, Passador L, Iglewski BH. RsaL, a novel repressor of virulence gene expression in Pseudomonas aeruginosa. J Bacteriol. 1999 Apr;181(7):2175-84. (1999) Abstract

Preston MJ, Seed PC, Toder DS, Iglewski BH, Ohman DE, Gustin JK, Goldberg JB, Pier GB. Contribution of proteases and LasR to the virulence of Pseudomonas aeruginosa during corneal infections. Infect Immun. 1997 Aug;65(8):3086-90. (1997) Abstract

Pesci EC, Pearson JP, Seed PC, Iglewski BH. Regulation of las and rhl quorum sensing in Pseudomonas aeruginosa. J Bacteriol. 1997 May;179(10):3127-32. (1997) Abstract

Seed PC, Passador L, Iglewski BH. Activation of the Pseudomonas aeruginosa lasI gene by LasR and the Pseudomonas autoinducer PAI: an autoinduction regulatory hierarchy. J Bacteriol. 1995 Feb;177(3):654-9. (1995) Abstract