RT Journal Article SR Electronic T1 An essential mycolate remodeling program for mycobacterial adaptation in host cells JF bioRxiv FD Cold Spring Harbor Laboratory SP 354431 DO 10.1101/354431 A1 Eliza J.R. Peterson A1 Rebeca Bailo A1 Alissa C. Rothchild A1 Mario Arrieta-Ortiz A1 Amardeep Kaur A1 Min Pan A1 Dat Mai A1 Charlotte Cooper A1 Alan Aderem A1 Apoorva Bhatt A1 Nitin S. Baliga YR 2018 UL http://biorxiv.org/content/early/2018/06/22/354431.abstract 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 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/A2 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.One Sentence Summary Novel technology (Path-seq) discovers cell wall remodeling program during Mycobacterium tuberculosis infection of macrophages