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Journal of Bacteriology, December 2009, p. 7165-7173, Vol. 191, No. 23
0021-9193/09/$08.00+0     doi:10.1128/JB.00903-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Penetration of the Blood-Brain Barrier by Bacillus anthracis Requires the pXO1-Encoded BslA Protein{triangledown}

Celia M. Ebrahimi,1 Justin W. Kern,2 Tamsin R. Sheen,1 Mohammad A. Ebrahimi-Fardooee,3 Nina M. van Sorge,4 Olaf Schneewind,2 and Kelly S. Doran1,4*

Department of Biology and Center for Microbial Sciences, San Diego State University, 5500 Campanile Dr., San Diego, California 92182,1 Department of Microbiology, University of Chicago, 920 East 58th Street, Chicago, Illinois,2 Department of Mathematics,3 Department of Pediatrics, University of California San Diego, 9500 Gilman Dr., La Jolla, California 920934

Received 10 July 2009/ Accepted 25 September 2009

Anthrax is a zoonotic disease caused by the gram-positive spore-forming bacterium Bacillus anthracis. Human infection occurs after the ingestion, inhalation, or cutaneous inoculation of B. anthracis spores. The subsequent progression of the disease is largely mediated by two native virulence plasmids, pXO1 and pXO2, and is characterized by septicemia, toxemia, and meningitis. In order to produce meningitis, blood-borne bacteria must interact with and breach the blood-brain barrier (BBB) that is composed of a specialized layer of brain microvascular endothelial cells (BMEC). We have recently shown that B. anthracis Sterne is capable of penetrating the BBB in vitro and in vivo, establishing the classic signs of meningitis; however, the molecular mechanisms underlying the central nervous system (CNS) tropism are not known. Here, we show that attachment to and invasion of human BMEC by B. anthracis Sterne is mediated by the pXO1 plasmid and an encoded envelope factor, BslA. The results of studies using complementation analysis, recombinant BslA protein, and heterologous expression demonstrate that BslA is both necessary and sufficient to promote adherence to brain endothelium. Furthermore, mice injected with the BslA-deficient strain exhibited a significant decrease in the frequency of brain infection compared to mice injected with the parental strain. In addition, BslA contributed to BBB breakdown by disrupting tight junction protein ZO-1. Our results identify the pXO1-encoded BslA adhesin as a critical mediator of CNS entry and offer new insights into the pathogenesis of anthrax meningitis.

* Corresponding author. Mailing address: Department of Biology, College of Sciences, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-4614. Phone: (619) 594-1867. Fax: (619) 594-5676. E-mail: kdoran{at}sciences.sdsu.edu

{triangledown} Published ahead of print on 9 October 2009.

Journal of Bacteriology, December 2009, p. 7165-7173, Vol. 191, No. 23
0021-9193/09/$08.00+0     doi:10.1128/JB.00903-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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