MyD88-dependent signaling protects against anthrax lethal toxin-induced impairment of intestinal barrier function.
MyD88-deficient mice were previously shown to have increased susceptibility to Bacillus anthracis infection relative to wild-type animals. To determine the mechanism by which MyD88 protects against B. anthracis infection, knockout mice were challenged with nonencapsulated, toxigenic B. anthracis or with anthrax toxins. MyD88-deficient mice had increased susceptibility to B. anthracis and anthrax lethal toxin but not to edema toxin. Lethal toxin alone induced marked multifocal intestinal ulcers in the knockout animals, compromising the intestinal epithelial barrier. The resulting enteric bacterial leakage in the knockout animals led to peritonitis and septicemia. Focal ulcers and erosion were also found in MyD88-heterozygous control mice but with far lower incidence and severity. B. anthracis infection also induced a similar enteric bacterial septicemia in MyD88-deficient mice but not in heterozygous controls. We show that lethal toxin and B. anthracis challenge induce bacteremia as a result of intestinal damage in MyD88-deficient mice. These results suggest that loss of the intestinal epithelial barrier and enteric bacterial septicemia may contribute to sensitizing MyD88-deficient mice to B. anthracis and that MyD88 plays a protective role against lethal toxin-induced impairment of intestinal barrier.
Bacterial Toxins and Therapeutics Section, Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases, NIH, 33 North Drive, Bldg 33, Bethesda, MD 20892, USA.
Shu
S
Okugawa
Mahtab
M
Moayeri
Michael A
MA
Eckhaus
Devorah
D
Crown
Sharmina
S
Miller-Randolph
Shihui
S
Liu
Shizuo
S
Akira
Stephen H
SH
Leppla
D000818:Animals; D000881:Anthrax / Q000382:microbiology / Q000473:pathology*; D000942:Antigens, Bacterial / Q000633:toxicity*; D016470:Bacteremia / Q000382:microbiology; D001427:Bacterial Toxins / Q000633:toxicity*; D020022:Genetic Predisposition to Disease; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013171:Spores, Bacterial
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C030325:anthrax toxin