Lung Epithelial Injury by B. Anthracis Lethal Toxin Is Caused by MKK-Dependent Loss of Cytoskeletal Integrity

Lehmann, Mandy; Noack, Deborah; Wood, Malcolm; Perego, Marta; Knaus, Ulla G.

doi:10.1371/journal.pone.0004755

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Lung Epithelial Injury by B. Anthracis Lethal Toxin Is Caused by MKK-Dependent Loss of Cytoskeletal Integrity

Published Date:

Mar 09 2009

Publisher's site:

http://dx.doi.org/10.1371/journal.pone.0004755

Source:

PLoS ONE. 2009; 4(3).

[PDF-1.60 MB]

Details:

Alternative Title:

PLoS ONE

Personal Author:

Lehmann, Mandy ; Noack, Deborah ; Wood, Malcolm ; Perego, Marta ; Knaus, Ulla G. ;

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:

[+]

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 ▼

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CDC Public Access

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