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

Publication Type:

Journal Article

Authors:

Peterson, Eliza JR; Bailo, Rebeca; Rothchild, Alissa C; Arrieta-Ortiz, Mario L; Kaur, Amardeep; Pan, Min; Mai, Dat; Abidi, Abrar A; Cooper, Charlotte; Aderem, Alan; Bhatt, Apoorva; Baliga, Nitin S

Source:

Molecular Systems Biology, Volume 15, p.e8584 (2019)

URL:

https://www.embopress.org/doi/abs/10.15252/msb.20188584

Keywords:

Gene Regulatory Networks, host–pathogen interactions, Mycobacterium tuberculosis, Path-seq, Systems Biology

Abstract:

<p>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&nbsp;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&nbsp;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.</p>