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 August 1, 2018; First 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 Vaccines

Enterotoxigenic Escherichia coli–blood group A interactions intensify diarrheal severity

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 1

Diarrheal severity is increased in blood group A–positive volunteers relative to those in the non-A blood groups.

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Diarrheal severity is increased in blood group A–positive volunteers rel...
(A) Development of severe diarrheal illness is accelerated in A blood group hosts. Kaplan-Meier curves indicate the proportion of subjects treated following the development of severe diarrheal illness in volunteers belonging to A and non-A blood groups. Time-to-treatment data were available for 79 of the 106 subjects (18 subjects in the A blood group and 61 subjects in the non-A group). Data were censored at 120 hours, when all remaining untreated individuals received antibiotics to clear their infection. P = 0.015, log-rank (Mantel-Cox) testing. (B) Individuals of A blood group are more likely to develop MSD. Shown are relative risk data from 4 independent controlled human infection model challenge studies of H10407 involving a total of 106 volunteers. Study numbers at left refer to ClinicalTrials.gov designations. Box size indicates relative study size, and lines represent 95% CIs for the relative risk of severe diarrhea. The width of the diamond indicates the 95% CIs for the pooled effect. The relative risk (pooled fixed effects) of MSD illness dichotomized by A (blood groups A and AB) vs. non-A (O and B) was 1.441 (95% CI, 1.097 to 1.893; P = 0.009). Cochran’s Q test of heterogeneity was insignificant (P = 0.667, Q = 1.5682, df = 3).