comprehensive functional analysis of mycobacterium tuberculosis toxin-antitoxin systems implications for pathogenesis, stress responses, and evolution结核分枝杆菌toxin-antitoxin综合功能分析系统对病机、应激反应、进化.pdfVIP

Comprehensive Functional Analysis of Mycobacterium tuberculosis Toxin-Antitoxin Systems: Implications for Pathogenesis, Stress Responses, and Evolution Holly R. Ramage1,2, Lynn E. Connolly1,2,3, Jeffery S. Cox1,2* 1 Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America, 2 Program in Microbial Pathogenesis and Host Defense, University of California San Francisco, San Francisco, California, United States of America, 3 Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, California, United States of America Abstract Toxin-antitoxin (TA) systems, stress-responsive genetic elements ubiquitous in microbial genomes, are unusually abundant in the major human pathogen Mycobacterium tuberculosis. Why M. tuberculosis has so many TA systems and what role they play in the unique biology of the pathogen is unknown. To address these questions, we have taken a comprehensive approach to identify and functionally characterize all the TA systems encoded in the M. tuberculosis genome. Here we show that 88 putative TA system candidates are present in M. tuberculosis, considerably more than previously thought. Comparative genomic analysis revealed that the vast majority of these systems are conserved in the M. tuberculosis complex (MTBC), but largely absent from other mycobacteria, including close relatives of M. tuberculosis. We found that many of the M. tuberculosis TA systems are located within discernable genomic islands and were thus likely acquired recently via horizontal gene transfer. We discovered a novel TA system located in the core genome that is conserved across the genus, suggesting that it may fulfill a role common to all mycobacteria. By expressing each of t