title: Secreted transcription factor controls Mycobacterium tuberculosis virulence.
abstract: Bacterial pathogens trigger specialized virulence factor secretion systems on encountering host cells. The ESX-1 protein secretion system of Mycobacterium tuberculosis-the causative agent of the human disease tuberculosis-delivers bacterial proteins into host cells during infection and is critical for virulence, but how it is regulated is unknown. Here we show that EspR (also known as Rv3849) is a key regulator of ESX-1 that is required for secretion and virulence in mice. EspR activates transcription of an operon that includes three ESX-1 components, Rv3616c-Rv3614c, whose expression in turn promotes secretion of ESX-1 substrates. EspR directly binds to and activates the Rv3616c-Rv3614c promoter and, unexpectedly, is itself secreted from the bacterial cell by the ESX-1 system that it regulates. Efflux of the DNA-binding regulator results in reduced Rv3616c-Rv3614c transcription, and thus reduced ESX-1 secretion. Our results reveal a direct negative feedback loop that regulates the activity of a secretion system essential for virulence. As the virulence factors secreted by the ESX-1 system are highly antigenic, fine control of secretion may be critical to successful infection.
authors.affiliation: Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, 600 16th Street, Campus Box 2200, San Francisco, California 94143-2200, USA.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Raghavan
authors.forename: Paolo
authors.initials: P
authors.lastname: Manzanillo
authors.forename: Kaman
authors.initials: K
authors.lastname: Chan
authors.forename: Cole
authors.initials: C
authors.lastname: Dovey
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Cox
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000472:pathogenicity*; D009876:Operon / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014774:Virulence / Q000235:genetics; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D014157:Transcription Factors; D037521:Virulence Factors