Details:

Alternative Title:
PLoS ONE
Publisher's site:
http://dx.doi.org/10.1371/journal.pone.0004755
Personal Author:
Lehmann, Mandy ; Noack, Deborah ; Wood, Malcolm ; Perego, Marta ; Knaus, Ulla G. ;
Lehmann, Mandy ; Noack, Deborah ; Wood, Malcolm ; Perego, Marta ; Knaus, Ulla G. ; Less -
Description:
Bacillus anthracis lethal toxin (LT) is a key virulence factor of anthrax and contributes significantly to the in vivo pathology. The enzymatically active component is a Zn(2+)-dependent metalloprotease that cleaves most isoforms of mitogen-activated protein kinase kinases (MKKs). Using ex vivo differentiated human lung epithelium we report that LT destroys lung epithelial barrier function and wound healing responses by immobilizing the actin and microtubule network. Long-term exposure to the toxin generated a unique cellular phenotype characterized by increased actin filament assembly, microtubule stabilization, and changes in junction complexes and focal adhesions. LT-exposed cells displayed randomly oriented, highly dynamic protrusions, polarization defects and impaired cell migration. Reconstitution of MAPK pathways revealed that this LT-induced phenotype was primarily dependent on the coordinated loss of MKK1 and MKK2 signaling. Thus, MKKs control fundamental aspects of cytoskeletal dynamics and cell motility. Even though LT disabled repair mechanisms, agents such as keratinocyte growth factor or dexamethasone improved epithelial barrier integrity by reducing cell death. These results suggest that co-administration of anti-cytotoxic drugs may be of benefit when treating inhalational anthrax.
Subject:
[+]
Actin Cytoskeleton
Antigens, Bacterial
Apoptosis
Bacterial Toxins
Blotting, Western
Bronchi
Cell Adhesion
Cell Biology/Cell Adhesion
Cell Membrane Permeability
Cell Movement
Cells, Cultured
Cell Survival
Cytoskeleton
Epithelial Cells
Fluorescent Antibody Technique
GTP Phosphohydrolases
Humans
Lentivirus
Lung Injury
Metalloendopeptidases
Mitogen-Activated Protein Kinase Kinases
Research Article
Wound Healing

Source:
PLoS ONE. 2009 ; 4(3).;
Pubmed ID:
19270742
Pubmed Central ID:
PMC2649448
Document Type:
Journal Article ;
Funding:
AI024838/AI/NIAID NIH HHS/United States ; AI055860/AI/NIAID NIH HHS/United States ; AI077042/AI/NIAID NIH HHS/United States ; CI000095/CI/NCPDCID CDC HHS/United States ; GM019416/GM/NIGMS NIH HHS/United States ; ... More +
AI024838/AI/NIAID NIH HHS/United States ; AI055860/AI/NIAID NIH HHS/United States ; AI077042/AI/NIAID NIH HHS/United States ; CI000095/CI/NCPDCID CDC HHS/United States ; GM019416/GM/NIGMS NIH HHS/United States ; GM055594/GM/NIGMS NIH HHS/United States ; Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:9543e9a5ce894a6271b33ca710257fbe5ca3a1e69b833b2046ddfa12ddb4d7a0
File Type:

Supporting Files

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