title: Anthrax lethal toxin disrupts intestinal barrier function and causes systemic infections with enteric bacteria.
abstract: A variety of intestinal pathogens have virulence factors that target mitogen activated protein kinase (MAPK) signaling pathways, including Bacillus anthracis. Anthrax lethal toxin (LT) has specific proteolytic activity against the upstream regulators of MAPKs, the MAPK kinases (MKKs). Using a murine model of intoxication, we show that LT causes the dose-dependent disruption of intestinal epithelial integrity, characterized by mucosal erosion, ulceration, and bleeding. This pathology correlates with an LT-dependent blockade of intestinal crypt cell proliferation, accompanied by marked apoptosis in the villus tips. C57BL/6J mice treated with intravenous LT nearly uniformly develop systemic infections with commensal enteric organisms within 72 hours of administration. LT-dependent intestinal pathology depends upon its proteolytic activity and is partially attenuated by co-administration of broad spectrum antibiotics, indicating that it is both a cause and an effect of infection. These findings indicate that targeting of MAPK signaling pathways by anthrax LT compromises the structural integrity of the mucosal layer, serving to undermine the effectiveness of the intestinal barrier. Combined with the well-described immunosuppressive effects of LT, this disruption of the intestinal barrier provides a potential mechanism for host invasion via the enteric route, a common portal of entry during the natural infection cycle of Bacillus anthracis.
authors.affiliation: Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland, United States of America.
authors.forename: Chen
authors.initials: C
authors.lastname: Sun
authors.forename: Hui
authors.initials: H
authors.lastname: Fang
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.forename: Roger D
authors.initials: RD
authors.lastname: Auth
authors.forename: Nayana
authors.initials: N
authors.lastname: Patel
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Murray
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Snoy
authors.forename: David M
authors.initials: DM
authors.lastname: Frucht
mesh_terms: D000818:Animals; D000881:Anthrax / Q000209:etiology / Q000473:pathology; D000942:Antigens, Bacterial / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001408:Bacillus anthracis / Q000472:pathogenicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004756:Enterobacteriaceae Infections / Q000209:etiology* / Q000473:pathology; D005260:Female; D054884:Host-Pathogen Interactions; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin