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

Research output: Contribution to journalArticlepeer-review

Authors

  • Eliza Jr Peterson
  • Alissa C Rothchild
  • Mario L Arrieta‐ortiz
  • Amardeep Kaur
  • Min Pan
  • Dat Mai
  • Abrar A Abidi
  • Charlotte Cooper
  • Alan Aderem
  • Nitin S Baliga

Colleges, School and Institutes

Abstract

The success of Mycobacterium tuberculosis (MTB) stems from its ability to remain hidden from the immune system within macrophages. Here, we report a new technology (Path-seq) to sequence miniscule amounts of MTB transcripts within up to million-fold excess host RNA. Using Path-seq and regulatory network analyses, we have discovered a novel transcriptional program for in vivo mycobacterial cell wall remodeling when the pathogen infects alveolar macrophages in mice. We have discovered that MadR transcriptionally modulates two mycolic acid desaturases desA1/desA2 to initially promote cell wall remodeling upon in vitro macrophage infection and, subsequently, reduces mycolate biosynthesis upon entering dormancy. We demonstrate that disrupting MadR program is lethal to diverse mycobacteria making this evolutionarily conserved regulator a prime antitubercular target for both early and late stages of infection.

Bibliographic note

© 2019 The Authors. Published under the terms of the CC BY 4.0 license.

Details

Original languageEnglish
Article numbere8584
Number of pages19
JournalMolecular Systems Biology
Volume15
Issue number3
Publication statusPublished - 1 Mar 2019

Keywords

  • gene regulatory networks, host–pathogen interactions, Mycobacterium tuberculosis, Path-seq, systems biology