bacillus anthracis protease inha increases blood-brain barrier permeability and contributes to cerebral hemorrhages炭疽杆菌蛋白酶韩国仁荷增加血脑屏障通透性,导致脑出血.pdf

Bacillus anthracis Protease InhA Increases Blood-Brain Barrier Permeability and Contributes to Cerebral Hemorrhages 1¤ 1 2 3 1 Dhritiman V. Mukherjee , Jessica H. Tonry , Kwang Sik Kim , Nalini Ramarao , Taissia G. Popova , 1 1 1 Charles Bailey , Serguei Popov *, Myung-Chul Chung * 1 National Center for Biodefense and Infectious Diseases, Department of Molecular and Microbiology, George Mason University, Manassas, Virginia, United States of ´ America, 2 Division of Pediatric Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America, 3 Unite MICALIS/GME, ` INRA, La Miniere, Guyancourt, France Abstract Hemorrhagic meningitis is a fatal complication of anthrax, but its pathogenesis remains poorly understood. The present study examined the role of B. anthracis-secreted metalloprotease InhA on monolayer integrity and permeability of human brain microvasculature endothelial cells (HBMECs) which constitute the blood-brain barrier (BBB). Treatment of HBMECs with purified InhA resulted in a time-dependent decrease in trans-endothelial electrical resistance (TEER) accompanied by zonula occluden-1 (ZO-1) degradation. An InhA-expressing B. subtilis exhibited increased permeability of HBMECs, which did not occur with the isogenic inhA deletion mutant (DinhA) of B. anthracis, compared with the corresponding wild-type strain. Mice intravenously administered with purified InhA or nanoparticles-conjugated to InhA demonstrated