TY - JOUR TI - Path‐seq identifies an essential mycolate remodeling program for mycobacterial host adaptation AU - Peterson, Eliza JR AU - Bailo, Rebeca AU - Rothchild, Alissa C. AU - Arrieta‐Ortiz, Mario L. AU - Kaur, Amardeep AU - Pan, Min AU - Mai, Dat AU - Abidi, Abrar A. AU - Cooper, Charlotte AU - Aderem, Alan AU - Bhatt, Apoorva AU - Baliga, Nitin S. T2 - Molecular Systems Biology AB - 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. Synopsis Embedded Image A new method, Path‐seq, deepens the coverage of pathogen transcripts from infected host cells. It measures non‐coding transcripts, simultaneously profiles host‐pathogen transcriptomes, and is sensitive enough to explore pathogen gene expression in vivo. Path‐seq features the enrichment (> 100‐fold) of pathogen transcripts using biotinylated oligonucleotide baits complementary to the pathogen transcriptome.Path‐seq and regulatory network analyses reveal infection‐specific regulatory networks for Mycobacterium tuberculosis.The mycolic acid desaturase regulator, MadR, controls the expression of desaturases, desA1/A2, that likely play a role in the composition and levels of cell wall mycolates during M. tuberculosis infection of host cells. DA - 2019/03/01/ PY - 2019 DO - 10.15252/msb.20188584 DP - msb.embopress.org VL - 15 IS - 3 SP - e8584 LA - en SN - 1744-4292, 1744-4292 UR - http://msb.embopress.org/content/15/3/e8584 Y2 - 2019/03/04/19:43:43 KW - Mycobacterium tuberculosis KW - Path‐seq KW - gene regulatory networks KW - host–pathogen interactions KW - systems biology ER -