anthrax toxins inhibit neutrophil signaling pathways in brain endothelium and contribute to the pathogenesis of meningitis炭疽毒素抑制中性粒细胞的大脑内皮细胞信号通路,导致脑膜炎的发病机制.pdfVIP

Anthrax Toxins Inhibit Neutrophil Signaling Pathways in Brain Endothelium and Contribute to the Pathogenesis of Meningitis 2 1 2 1 3 Nina M. van Sorge , Celia M. Ebrahimi , Shauna M. McGillivray , Darin Quach , Mojgan Sabet , Donald G. Guiney3, Kelly S. Doran1,2* 1 Department of Biology and Center for Microbial Sciences, San Diego State University, San Diego, California, United States of America, 2 Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America, 3 Department of Medicine, University of California San Diego, La Jolla, California, United States of America Abstract Background: Anthrax meningitis is the main neurological complication of systemic infection with Bacillus anthracis approaching 100% mortality. The presence of bacilli in brain autopsies indicates that vegetative bacteria are able to breach the blood-brain barrier (BBB). The BBB represents not only a physical barrier but has been shown to play an active role in initiating a specific innate immune response that recruits neutrophils to the site of infection. Currently, the basic pathogenic mechanisms by which B. anthracis penetrates the BBB and causes anthrax meningitis are poorly understood. Methodology/Principal Findings: Using an in vitro BBB model, we show for the first time that B. anthracis efficiently invades human brain microvascular endothelial cells (hBMEC), the single cell layer that comprises the BBB. Furthermore, transcriptional profiling of hBMEC during infection with B. anthracis revealed downregulation of 270 (87%) genes, specifically key neutrophil chemoattractants IL-8, CXCL1 (Groa) and CXCL2 (Grob