Transcriptional adaptation of <i>Mycobacterium tuberculosis</i> that survives prolonged multi-drug treatment in mice

Abstract

A major reason that curing tuberculosis requires prolonged treatment is that drug exposure changes bacterial phenotypes. The physiologic adaptations of <i>Mycobacterium tuberculosis</i> that survive drug exposure <i>in vivo</i> have been obscure due to low sensitivity of existing methods in drug-treated animals. Using the novel SEARCH-TB RNA-seq platform, we elucidated <i>Mycobacterium tuberculosis</i> phenotypes in mice treated for with the global standard 4-drug regimen and compared them with the effect of the same regimen <i>in vitro</i>. This first view of the transcriptome of the minority <i>Mycobacterium tuberculosis</i> population that withstands treatment <i>in vivo</i> reveals adaptation of a broad range of cellular processes, including a shift in metabolism and cell wall modification. Surprisingly, the change in gene expression induced by treatment <i>in vivo</i> and <i>in vitro</i> was largely similar. This apparent "portability" from <i>in vitro</i> to the mouse provides important new context for <i>in vitro</i> transcriptional analyses that may support early preclinical drug evaluation.