title: Diminished Clostridium difficile toxin A sensitivity in newborn rabbit ileum is associated with decreased toxin A receptor.
abstract: Human infants are relatively resistant to Clostridium difficile-associated diarrhea and colitis compared to adults. In that toxin A is the major cause of intestinal damage with this organism, we compared toxin A receptor binding and biological effects in newborn vs adult rabbit ileum. Purified toxin A (M(r) 308 kD) was labeled with tritium or biotin with full retention of biologic activity. Appearance of specific toxin A brush border (BB) binding was strongly age dependent with minimal [3H]toxin A specific binding at 2 and 5 d of life, followed by gradual increase in binding to reach adult levels at 90 d. Absence of toxin A binding sites in newborn and presence in adult rabbits was confirmed by immunohistochemical studies using biotinylated toxin A. Toxin A (50 ng to 20 micrograms/ml) inhibited protein synthesis in 90-d-old rabbit ileal loops in a dose-dependent fashion. In contrast, inhibition of protein synthesis in 5-d-old rabbit ileum occurred only at the highest toxin A doses (5 and 20 micrograms/ml) and at all doses tested was significantly less than the adult rabbit ileum. In addition, toxin A (5 micrograms/ml) caused severe mucosal damage in adult rabbit ileal explants but had no discernable morphologic effect on 5-d-old rabbit intestine. Our data indicate that newborn rabbit intestine lacks BB receptors for toxin A. The absence of the high-affinity BB receptor for toxin A in the newborn period may explain lack of biologic responsiveness to purified toxin, and the absence of disease in human infants infected with this pathogen.
authors.affiliation: Department of Pathology, University Hospital, Boston University School of Medicine, Massachusetts 02118.
authors.forename: R
authors.initials: R
authors.lastname: Eglow
authors.forename: C
authors.initials: C
authors.lastname: Pothoulakis
authors.forename: S
authors.initials: S
authors.lastname: Itzkowitz
authors.forename: E J
authors.initials: EJ
authors.lastname: Israel
authors.forename: C J
authors.initials: CJ
authors.lastname: O'Keane
authors.forename: D
authors.initials: D
authors.lastname: Gong
authors.forename: N
authors.initials: N
authors.lastname: Gao
authors.forename: Y L
authors.initials: YL
authors.lastname: Xu
authors.forename: W A
authors.initials: WA
authors.lastname: Walker
authors.forename: J T
authors.initials: JT
authors.lastname: LaMont
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001427:Bacterial Toxins / Q000633:toxicity*; D001665:Binding Sites; D016360:Clostridioides difficile / Q000378:metabolism*; D004768:Enterotoxins / Q000378:metabolism / Q000633:toxicity*; D006162:Guanylate Cyclase; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008871:Microvilli / Q000378:metabolism; D014176:Protein Biosynthesis; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000032:analysis*; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled; D018000:Receptors, Peptide
chemical_list: D001427:Bacterial Toxins; D004768:Enterotoxins; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; C041348:tcdA protein, Clostridium difficile; D006162:Guanylate Cyclase; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled