Secreted transcription factor controls Mycobacterium tuberculosis virulence

Sridharan Raghavan, Paolo Manzanillo, Kaman Chan, Cole Dovey and Jeffery S. Cox ()
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Sridharan Raghavan: Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, 600 16th Street, Campus Box 2200, San Francisco, California 94143-2200, USA
Paolo Manzanillo: Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, 600 16th Street, Campus Box 2200, San Francisco, California 94143-2200, USA
Kaman Chan: Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, 600 16th Street, Campus Box 2200, San Francisco, California 94143-2200, USA
Cole Dovey: Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, 600 16th Street, Campus Box 2200, San Francisco, California 94143-2200, USA
Jeffery S. Cox: Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, 600 16th Street, Campus Box 2200, San Francisco, California 94143-2200, USA

Nature, 2008, vol. 454, issue 7205, 717-721

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature07219

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