Diminished Clostridium difficile toxin A sensitivity in newborn rabbit ileum is associated with decreased toxin A receptor.
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.
Eglow
R
R
Department of Pathology, University Hospital, Boston University School of Medicine, Massachusetts 02118.
Pothoulakis
C
C
Itzkowitz
S
S
Israel
E J
EJ
O'Keane
C J
CJ
Gong
D
D
Gao
N
N
Xu
Y L
YL
Walker
W A
WA
LaMont
J T
JT
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
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