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PMID:22438953
| Citation |
Sun, C, Fang, H, Xie, T, Auth, RD, Patel, N, Murray, PR, Snoy, PJ and Frucht, DM (2012) Anthrax lethal toxin disrupts intestinal barrier function and causes systemic infections with enteric bacteria. PLoS ONE 7:e33583 |
|---|---|
| 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. |
| Links |
PubMed PMC3306423 Online version:10.1371/journal.pone.0033583 |
| Keywords |
Animals; Anthrax/etiology; Anthrax/pathology; Antigens, Bacterial/toxicity; Apoptosis/drug effects; Bacillus anthracis/pathogenicity; Bacterial Toxins/toxicity; Cell Proliferation/drug effects; Disease Models, Animal; Enterobacteriaceae Infections/etiology; Enterobacteriaceae Infections/pathology; Female; Host-Pathogen Interactions; Intestinal Mucosa/drug effects; Intestinal Mucosa/pathology; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL |
| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
|
involved_in |
GO:0009405: pathogenesis |
ECO:0000270: expression pattern evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
| GO:0006508: proteolysis |
ECO:0000314: |
P |
figure 5 demonstrated that "the specific proteolytic activity of lethal factor of the MKKs is required for the anti-proliferate and pro-apoptotic effects of lethal toxin on the intestinal epithelium" ; the data also established the proteolysis activity of lethal factor of Anthrax lethal toxin |
complete | ||||
| GO:0009405: pathogenesis |
ECO:0000270: |
P |
figure 2 - "in time course study, lethal toxin-induced pathological changes became evident in the intestine 48 hours post lethal toxin exposure. these changes included the onset of villous damage and minor hemorrhage. by 72 hours post lethal toxin exposure, focal areas showed marked destruction of the normal villous structures, accompanied by ares ulceration" |
complete | ||||
See also
References
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