anthrax lethal toxin disrupts intestinal barrier function and causes systemic infections with enteric bacteria炭疽致命的毒素会破坏肠道屏障功能和引起系统性感染肠道细菌.pdfVIP

Anthrax Lethal Toxin Disrupts Intestinal Barrier Function and Causes Systemic Infections with Enteric Bacteria 1 1 1 1 2 2¤ {3 Chen Sun , Hui Fang , Tao Xie , Roger D. Auth , Nayana Patel , Patrick R. Murray , Philip J. Snoy , David M. Frucht1* 1 Laboratory of Cell Biology, Division of Monoclonal Antibodies, Office of Biotechnology Products, Center for Drug Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland, United States of America, 2 Department of Laboratory Medicine, Warren Magnusen Clinical Center, National Institutes of Health, Bethesda, Maryland, United States of America, 3 Division of Veterinary Services, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland, United States of America Abstract A variety of intestinal pathogens have virulence factors that target mitogen activated protein kinase (MAPK) signaling pathways, including Bacillus anthracis. Anthrax lethal toxin (LT) has specific proteolytic activity against the upstream regulators of MAPKs, the MAPK kinases (MKKs). Using a murine model of intoxication, we show that LT causes the dose- dependent disruption of intestinal epithelial integrity, characterized by mucosal erosion, ulceration, and bleeding. This pathology correlates with an LT-dependent blockade of intestinal crypt cell proliferation, accompanied by marked apoptosis in the villus tips. C57BL/6J mice treated with intravenous LT nearly uniformly develop systemic infections with commensal enteric organisms within 72 hours of administration. LT-dependent intestinal pathology depends upon its proteolytic activi