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TcrXY is an acid-sensing two-component transcriptional regulator of Mycobacterium tuberculosis required for persistent infection

Author

Listed:
  • Miljan Stupar

    (The University of Queensland)

  • Lendl Tan

    (The University of Queensland)

  • Edward D. Kerr

    (The University of Queensland)

  • Christopher J. Voss

    (The University of Queensland)

  • Brian M. Forde

    (The University of Queensland)

  • Benjamin L. Schulz

    (The University of Queensland)

  • Nicholas P. West

    (The University of Queensland)

Abstract

The ability of Mycobacterium tuberculosis (Mtb) to persist in the host complicates and prolongs tuberculosis (TB) patient chemotherapy. Here we demonstrate that a neglected two-component system (TCS) of Mtb, TcrXY, is an autoregulated acid-sensing TCS that controls a functionally diverse 70-gene regulon required for bacterial persistence. Characterisation of two representatives of this regulon, Rv3706c and Rv3705A, implicate these genes as key determinants for the survival of Mtb in vivo by serving as important effectors to mitigate redox stress at acidic pH. We show that genetic silencing of the response regulator tcrX using CRISPR interference attenuates the persistence of Mtb during chronic mouse infection and improves treatment with the two front-line anti-TB drugs, rifampicin and isoniazid. We propose that targeting TcrXY signal transduction blocks the ability of Mtb to sense and respond to acid stress, resulting in a disordered program of persistence to render the organism vulnerable to existing TB chemotherapy.

Suggested Citation

  • Miljan Stupar & Lendl Tan & Edward D. Kerr & Christopher J. Voss & Brian M. Forde & Benjamin L. Schulz & Nicholas P. West, 2024. "TcrXY is an acid-sensing two-component transcriptional regulator of Mycobacterium tuberculosis required for persistent infection," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45343-7
    DOI: 10.1038/s41467-024-45343-7
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    1. Kaj M. Kreutzfeldt & Robert S. Jansen & Travis E. Hartman & Alexandre Gouzy & Ruojun Wang & Inna V. Krieger & Matthew D. Zimmerman & Martin Gengenbacher & Jansy P. Sarathy & Min Xie & Véronique Dartoi, 2022. "CinA mediates multidrug tolerance in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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