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Enterotoxigenic Escherichia coli–blood group A interactions intensify diarrheal severity
Pardeep Kumar, … , Mark Donowitz, James M. Fleckenstein
Pardeep Kumar, … , Mark Donowitz, James M. Fleckenstein
Published May 17, 2018
Citation Information: J Clin Invest. 2018;128(8):3298-3311. https://doi.org/10.1172/JCI97659.
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Research Article Infectious disease

Enterotoxigenic Escherichia coli–blood group A interactions intensify diarrheal severity

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Abstract

Enterotoxigenic Escherichia coli (ETEC) infections are highly prevalent in developing countries, where clinical presentations range from asymptomatic colonization to severe cholera-like illness. The molecular basis for these varied presentations, which may involve strain-specific virulence features as well as host factors, has not been elucidated. We demonstrate that, when challenged with ETEC strain H10407, originally isolated from a case of cholera-like illness, blood group A human volunteers developed severe diarrhea more frequently than individuals from other blood groups. Interestingly, a diverse population of ETEC strains, including H10407, secrete the EtpA adhesin molecule. As many bacterial adhesins also agglutinate red blood cells, we combined the use of glycan arrays, biolayer inferometry, and noncanonical amino acid labeling with hemagglutination studies to demonstrate that EtpA is a dominant ETEC blood group A–specific lectin/hemagglutinin. Importantly, we have also shown that EtpA interacts specifically with glycans expressed on intestinal epithelial cells from blood group A individuals and that EtpA-mediated bacterial-host interactions accelerate bacterial adhesion and effective delivery of both the heat-labile and heat-stable toxins of ETEC. Collectively, these data provide additional insight into the complex molecular basis of severe ETEC diarrheal illness that may inform rational design of vaccines to protect those at highest risk.

Authors

Pardeep Kumar, F. Matthew Kuhlmann, Subhra Chakraborty, A. Louis Bourgeois, Jennifer Foulke-Abel, Brunda Tumala, Tim J. Vickers, David A. Sack, Barbara DeNearing, Clayton D. Harro, W. Shea Wright, Jeffrey C. Gildersleeve, Matthew A. Ciorba, Srikanth Santhanam, Chad K. Porter, Ramiro L. Gutierrez, Michael G. Prouty, Mark S. Riddle, Alexander Polino, Alaullah Sheikh, Mark Donowitz, James M. Fleckenstein

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Figure 3

EtpA is a blood group A–specific hemagglutinin.

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EtpA is a blood group A–specific hemagglutinin.
(A) Binding of rEtpA to ...
(A) Binding of rEtpA to the surface of group A1 and A2 RBC ghosts relative to B and O RBCs is shown in FACS data and a graph. (B) RBC pull-down of rEtpA with different blood group ghost erythrocytes. Shown in the immunoblot is rEtpA-myc-his identified by anti-myc antibodies. (C) EtpA agglutinates A1 RBCs, but exhibits minimal or no hemagglutination activity with RBCs from those with A2, B, or O blood groups. The column on the right includes anti–A blood group antibodies as a positive control. (D) EtpA-mediated hemagglutination is dependent on terminal GalNac residues. A1 RBCS pretreated with α-N-acetylgalactosaminidase (top row) fail to agglutinate in the presence of rEtpA. Shown (row 2, left) are positive controls (no enzyme pretreatment) and blood group O–negative controls (bottom rows). (E) EtpA-coated latex microspheres (top row) agglutinate RBCs from blood group A, but not B or O. Bottom row shows BSA-coated particles as controls. Each of the images are representative of 3 experimental replicates. Original magnification, ×40.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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