Publication Date:
2019
Description:
〈p〉The success of 〈i〉Mycobacterium tuberculosis〈/i〉 (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 〈i〉in vivo〈/i〉 mycobacterial cell wall remodeling when the pathogen infects alveolar macrophages in mice. We have discovered that MadR transcriptionally modulates two mycolic acid desaturases 〈i〉desA1〈/i〉/〈i〉desA2〈/i〉 to initially promote cell wall remodeling upon 〈i〉in vitro〈/i〉 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〉
Electronic ISSN:
1744-4292
Topics:
Biology
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