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Path-seq identifies an essential mycolate remodeling program for mycobacterial host adaptation.

Eliza Jr Peterson1, Rebeca Bailo2, Alissa C Rothchild3

  • 1Institute for Systems Biology, Seattle, WA, USA.

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|March 6, 2019
PubMed
Summary
This summary is machine-generated.

We discovered a new way to study Mycobacterium tuberculosis (MTB) within host cells. This revealed a key regulator, MadR, controlling the bacterial cell wall, offering a new target for tuberculosis treatments.

Keywords:
Mycobacterium tuberculosisPath‐seqgene regulatory networkshost–pathogen interactionssystems biology

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Area of Science:

  • Microbiology
  • Immunology
  • Genomics

Background:

  • Mycobacterium tuberculosis (MTB) evades the host immune system by residing within macrophages.
  • Understanding MTB's survival mechanisms within host cells is crucial for developing effective treatments.

Purpose of the Study:

  • To develop a novel sequencing technology (Path-seq) for analyzing minimal MTB RNA in the presence of excess host RNA.
  • To identify novel transcriptional programs involved in MTB's adaptation and survival within macrophages.

Main Methods:

  • Development and application of Path-seq technology for transcriptomic analysis.
  • Regulatory network analysis to identify key transcriptional regulators.
  • In vitro and in vivo studies using mouse models of infection.

Main Results:

  • Path-seq enabled sequencing of minute MTB transcripts amidst overwhelming host RNA.
  • A novel transcriptional program for in vivo mycobacterial cell wall remodeling was identified.
  • The transcription factor MadR was found to modulate mycolic acid desaturases (desA1/desA2), promoting cell wall remodeling during infection and reducing it during dormancy.

Conclusions:

  • MadR controls a conserved mycobacterial cell wall remodeling program essential for survival during infection and dormancy.
  • Disruption of the MadR pathway is lethal to various mycobacteria.
  • MadR represents a promising, evolutionarily conserved antitubercular target for all stages of infection.