James Fleckenstein, MD

Internal Medicine
Infectious Diseases
Molecular Microbiology

Molecular Microbiology and Microbial Pathogenesis Program
Plant and Microbial Biosciences Program

  • 314-362-9218

  • 314-362-9219

  • 314-362-9230

  • McDonnell Pediatric Research Bldg

  • jfleckenstein@wustl.edu

  • https://sites.wustl.edu/flecklab

  • @eteclab

  • enterotoxigenic Escherichia coli; microbial pathogenesis; vaccine development; diarrheal disease

  • Molecular investigation of enterotoxigenic Escherichia coli (ETEC)

Research Abstract:

Research in our laboratory focuses on the molecular pathogenesis of enterotoxigenic Escherichia coli (ETEC). These organisms are a major cause of mortality in young children due to diarrheal illness in developing countries, and are perennially the most common etiology of diarrhea in travelers. ETEC constitute a diverse E. coli “pathotype” that share in the ability to effectively deliver heat-labile (LT) and/or heat-stable (ST) toxins to respectively activate cAMP and cGMP production in host intestinal cells. Both of these cyclic nucleotides activate protein kinases to phosphorylate and activate the cystic fibrosis transmembrane conductance regulator (CFTR) ultimately leading to a net loss of salt and water in the small intestine to cause the watery cholera-like diarrhea characteristic of these pathogens. Although ETEC have been a target of vaccine development efforts for several decades, progress has been hampered by heterogeneity in key targets (namely plasmid-encoded fimbrial antigens known as colonization factors or CFs), incomplete protection afforded by anti-LT immunity, and the poor immunogenicity of ST, (small molecules typically ~18-19 amino acids).

Studies in the lab use a variety of molecular techniques and in vitro and in vivo models to elucidate the role of novel virulence factors in several key steps essential in the pathogenesis of these organisms: bacterial adhesion, intestinal colonization, and finally toxin delivery. Projects involving genome, transcriptome, and immuno-proteome analysis of these pathogens seek to accelerate identification of potential vaccine targets. The principal long-term goal of these studies is to provide additional molecular details to aid rational selection of target antigens and inform future vaccine development efforts for these important pathogens.

Selected Publications:

Interrogation of a live-attenuated enterotoxigenic Escherichia coli vaccine highlights features unique to wild-type infection.
Chakraborty S, Randall A, Vickers TJ, Molina D, Harro CD, DeNearing B, Brubaker J, Sack DA, Bourgeois AL, Felgner PL, Liang X, Mani S, Wenzel H, Townsend RR, Gilmore PE, Darsley MJ, Rasko DA, Fleckenstein JM. NPJ Vaccines. 2019 Aug 28;4:37. doi: 10.1038/s41541-019-0131-7. eCollection 2019.PMID: 31482013

CEACAMs serve as toxin-stimulated receptors for enterotoxigenic Escherichia coli.
Sheikh A, Tumala B, Vickers TJ, Alvarado D, Ciorba MA, Bhuiyan TR, Qadri F, Singer BB,Fleckenstein JM. Proc Natl Acad Sci U S A. 2020 Nov 2:202012480. doi: 10.1073/pnas.2012480117. Online ahead of print.PMID: 33139570

Enterotoxigenic Escherichia coli blood group A interactions intensify diarrheal severity.
Kumar P, Kuhlmann FM, Chakroborty S, Bourgeois AL, Foulke-Abel J, Tumala B, Vickers TJ, Sack DA, DeNearing B, Harro CD, Wright WS, Gildersleeve JC, Ciorba MA, Santhanam S, Porter CK, Gutierrez RL, Prouty MG, Riddle MS, Polino A, Sheikh A, Donowitz M, Fleckenstein JM. J Clin Invest. 2018 May 17. pii: 97659. doi: 10.1172/JCI97659. [Epub ahead of print]
PMID: 29771685

Conservation and immunogenicity of novel antigens in diverse isolates of enterotoxigenic Escherichia coli.
Luo Q, Qadri F, Kansal R, Rasko DA, Sheikh A, Fleckenstein JM. PLoS Negl Trop Dis. 2015 Jan 28;9(1):e0003446.

Novel antigens for enterotoxigenic Escherichia coli (ETEC) vaccines.
Fleckenstein JM, Sheikh A, Qadri F. Expert Rev Vaccines 2014; 13(5):631-9 .

EatA, an Immununogenic Protective Antigen of Enterotoxigenic Escherichia coli Degrades Intestinal Mucin.
Kumar P, Luo Q, Vickers TJ, Sheikh A, Lewis WG, Fleckenstein JM. Infect Immun Infect Immun. 2014 Feb;82(2):509-21. doi: 10.1128/IAI.01106-13. PMID: 24218479

Cooperative role of antibodies against heat-labile toxin and the EtpA adhesin in preventing toxin delivery and intestinal colonization by enterotoxigenic Escherichia coli.
Roy K, Hamilton DJ, Fleckenstein JM. Clin Vaccine Immunol. 2012 Oct;19(10):1603-8. Epub 2012 Aug 8.0

Directed evaluation of enterotoxigenic Escherichia coli autotransporter proteins as putative vaccine candidates.
Harris JA, Roy K, Woo-Rasberry V, Hamilton DJ, Kansal R, Qadri F, Fleckenstein JM. PLoS Negl Trop Dis. 2011 Dec;5(12):e1428. Epub 2011 Dec 6. PMID: 22163060

Outer membrane vesicles induce immune responses to virulence proteins and protect against colonization by enterotoxigenic Escherichia coli.
Roy K, Hamilton DJ, Munson GP, Fleckenstein JM. Clin Vaccine Immunol. 2011 Nov;18(11):1803-8. Epub 2011 Sep 7. PMID: 21900530

Adhesin degradation accelerates delivery of heat-labile toxin by enterotoxigenic Escherichia coli.
Roy K, Kansal R, Bartels SR, Hamilton DJ, Shaaban S, Fleckenstein JM. J Biol Chem. 2011 Aug 26;286(34):29771-9. Epub 2011 Jul 8. PMID: 21757737

Enterotoxigenic Escherichia coli elicits immune responses to multiple surface proteins.
Roy K, Bartels S, Qadri F, Fleckenstein JM. Infect Immun. 2010 Jul;78(7):3027-35 PMID: 20457787

Molecular mechanisms of enterotoxigenic Escherichia coli infection.
Fleckenstein JM, Hardwidge PR, Munson GP, Rasko DA, Sommerfelt H, Steinsland H. Microbes Infect. 2010 Feb;12(2):89-98. PMID: 19883790

Vaccination with EtpA glycoprotein or flagellin protects against colonization with enterotoxigenic Escherichia coli in a murine model. Roy K, Hamilton D, Ostmann MM, Fleckenstein JM. Vaccine. 2009 Jul 23;27(34):4601-8. PMID: 19523914

Enterotoxigenic Escherichia coli EtpA mediates adhesion between flagella and host cells.
Roy K, Hilliard GM, Hamilton DJ, Luo J, Ostmann MM, Fleckenstein JM. Nature. 2009 Jan 29;457(7229):594-8. PMID: 19060885

Last Updated: 4/2/2022 11:39:53 AM

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