title: Contribution of adenosine A(2B) receptors in Clostridium difficile intoxication and infection.
abstract: Clostridium difficile toxins A (TcdA) and B (TcdB) induce a pronounced systemic and intestinal inflammatory response. A(2B) adenosine receptors (A(2B)ARs) are the predominant adenosine receptors in the intestinal epithelium. We investigated whether A(2B)ARs are upregulated in human intestinal cells by TcdA or TcdB and whether blockade of A(2B)ARs can ameliorate C. difficile TcdA-induced enteritis and alter the outcome of C. difficile infection (CDI). Adenosine receptor subtype (A(1), A(2A), A(2B), and A(3)) mRNAs were assayed in HCT-8 cells. Ileal loops from wild-type rabbits and mice and A(2B)AR(-/-) mice were treated with TcdA, with or without the selective A(2B)AR antagonist ATL692 or PSB1115. A murine model of CDI was used to determine the effect of A(2B)AR deletion or blockade with the orally available agent ATL801, on clinical outcome, histopathology and intestinal interleukin-6 (IL-6) expression from infection. TcdA and TcdB upregulated A(2B)AR gene expression in HCT-8 cells. ATL692 decreased TcdA-induced secretion and epithelial injury in rabbit ileum. Deletion of A(2B)ARs reduced secretion and histopathology in TcdA-challenged mouse ileum. Deletion or blockade of A(2B)ARs reduced histopathology, IL-6 expression, weight loss, diarrhea, and mortality in C. difficile-infected mice. A(2B)ARs mediate C. difficile toxin-induced enteritis and disease. Inhibition of A(2B)AR activation may be a potential strategy to limit morbidity and mortality from CDI.
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia, USA. ca6t@virginia.edu
authors.forename: Cirle A
authors.initials: CA
authors.lastname: Warren
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Li
authors.forename: Gina M
authors.initials: GM
authors.lastname: Calabrese
authors.forename: Rosemayre S
authors.initials: RS
authors.lastname: Freire
authors.forename: Snjezana
authors.initials: S
authors.lastname: Zaja-Milatovic
authors.forename: Edward
authors.initials: E
authors.lastname: van Opstal
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figler
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
authors.forename: Richard L
authors.initials: RL
authors.lastname: Guerrant
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology; D045744:Cell Line, Tumor; D016360:Clostridioides difficile / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D003106:Colon / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D004761:Enterocolitis, Pseudomembranous / Q000382:microbiology / Q000473:pathology; D004768:Enterotoxins / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007082:Ileum / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011817:Rabbits; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D043704:Receptor, Adenosine A2B; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile