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.

Phosphodiesterase 5 (PDE5) restricts intracellular cGMP accumulation during enterotoxigenic Escherichia coli infection

“…Measurement of intracellular cAMP and cGMP in HEMs colonized by H10407 was recently reported. 24,26 However, the characterization of infection-associated cyclic nucleotide efflux has not been explored in the HEM model. Additionally, evaluation of an approximate pathophysiological ST concentration for experimental reference has not been described.…”

“…Adoption of the two-dimensional human enteroid monolayer (HEM) culture on permeable supports has facilitated the modeling of numerous bacterial and viral-mediated gastrointestinal diseases, 20 - 23 including the specific affinity of ETEC H10407 for the blood group A antigen that enhances colonization and diarrheal susceptibility. 24 These findings highlight the importance of evaluating human biology using enteroids to better understand infectious diarrheal diseases.…”

Research in a time of enteroids and organoids: how the human gut model has transformed the study of enteric bacterial pathogens

“…As an example of using enteroids to interrogate mechanisms related to disease epidemiology, Kumar and Kuhlmann et al demonstrated that the ETEC adhesin EtpA targets polysaccharides with the blood group A surface antigen. 32 The study was driven by a meta-analysis of volunteer challenge studies that suggested ETEC caused more severe disease in individuals bearing the A type antigen. Blood group A donor jejunal and ileal enteroid monolayers were colonized more extensively by ETEC H10407 than monolayers derived from blood group B or O donors.…”

Heat-Stable Enterotoxins of Enterotoxigenic Escherichia coli and Their Impact on Host Immunity

“…For most of the fimbriae of the pig-specific ETEC strains the receptor has been identified [18]. However, for human ETEC strains, the epithelial interaction partners for their adhesins are only recently being unraveled [19]. Upon attachment to the epithelium, ETEC release heat-labile (LT) and/or heat-stable enterotoxins, that act upon intestinal enterocytes by disrupting the electrolyte homeostasis, resulting in fluid loss and eventually secretory diarrhea [15].…”