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Anthrax Edema Toxin Co-Opts IGF1R and EGFR Signaling to Promote Cell-Cell Barrier Dysfunction

37 Pages Posted: 9 Sep 2019 Sneak Peek Status: Under Review

See all articles by Prashant Jain

Prashant Jain

University of California, San Diego (UCSD) - Section of Cell and Developmental Biology

Mahtab Moayeri

National Institute of Allergy and Infectious Diseases (NIAID)

Annabel Guichard

University of California, San Diego (UCSD) - Section of Cell and Developmental Biology

Stephen Leppla

National Institute of Allergy and Infectious Diseases (NIAID)

Ethan Bier

University of California, San Diego (UCSD) - Section of Cell and Developmental Biology

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Abstract

Cell-cell barrier dysfunction induced by the anthrax edema toxin (ET) is central to bacterial dissemination and lethal vascular collapse during disease progression. Available treatments including antimicrobial and early-stage antitoxin measures do not prevent lethal anthrax toxemia during fulminant stages of infection. This study identifies cell-based therapeutic measures that target the late-stage intracellular activities of ET and their potential to mitigate consequences of ET toxemia. We uncover a critical involvement of IGF1R and EGFR in promoting ET-dependent barrier disruption through effects on cellular F-actin network that are separate from, but have an impact upon, previously characterized cAMP-mediated inhibition of vesicular trafficking. ET rapidly trans-activates IGF1R and EGFR, resulting in the activation of downstream effectors PI3K and MEK, and subsequently a Rac1- and cofilin-dependent actin remodeling. Finally, we provide in vivo pre-clinical validation of the therapeutic potential of PI3K, MEK and Rac1 inhibitors in preventing ET-dependent edema in a mouse footpad model.

Keywords: anthrax, edema toxin, antitoxin, barrier disruption, receptor transactivation, Cell-based therapy, IGF1R, EGFR

Suggested Citation

Jain, Prashant and Moayeri, Mahtab and Guichard, Annabel and Leppla, Stephen and Bier, Ethan, Anthrax Edema Toxin Co-Opts IGF1R and EGFR Signaling to Promote Cell-Cell Barrier Dysfunction (September 9, 2019). CELL-REPORTS-D-19-03424. Available at SSRN: https://ssrn.com/abstract=3449278 or http://dx.doi.org/10.2139/ssrn.3449278
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Prashant Jain

University of California, San Diego (UCSD) - Section of Cell and Developmental Biology

9500 Gilman Drive #108
La Jolla, CA 92093-0108
United States

Mahtab Moayeri

National Institute of Allergy and Infectious Diseases (NIAID)

Bethesda, MD 20892-9806
United States

Annabel Guichard

University of California, San Diego (UCSD) - Section of Cell and Developmental Biology

9500 Gilman Drive #108
La Jolla, CA 92093-0108
United States

Stephen Leppla

National Institute of Allergy and Infectious Diseases (NIAID)

Bethesda, MD 20892-9806
United States

Ethan Bier (Contact Author)

University of California, San Diego (UCSD) - Section of Cell and Developmental Biology ( email )

9500 Gilman Drive #108
La Jolla, CA 92093-0108
United States

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