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Secreted transcription factor controls Mycobacterium tuberculosis virulence

Author

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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)

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.

Suggested Citation

  • Sridharan Raghavan & Paolo Manzanillo & Kaman Chan & Cole Dovey & Jeffery S. Cox, 2008. "Secreted transcription factor controls Mycobacterium tuberculosis virulence," Nature, Nature, vol. 454(7205), pages 717-721, August.
    • Handle: RePEc:nat:nature:v:454:y:2008:i:7205:d:10.1038_nature07219
    DOI: 10.1038/nature07219
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    Cited by:

    1. Chun-Yu Lin & Tun-Chieh Chen & Po-Liang Lu & Chung-Chih Lai & Yi-Hsin Yang & Wei-Ru Lin & Pei-Ming Huang & Yen-Hsu Chen, 2013. "Effects of Gender and Age on Development of Concurrent Extrapulmonary Tuberculosis in Patients with Pulmonary Tuberculosis: A Population Based Study," PLOS ONE, Public Library of Science, vol. 8(5), pages 1-9, May.

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