Loss of thePPE71-esxX-esxY-PPE38locus drives adaptive transcriptional responses and hypervirulence ofMycobacterium tuberculosisLineage 2

Mycobacterium tuberculosis(M.tb) is remarkable for its immense global disease burden and low mutation rate. Despite strong selective pressure,M.tbshows frequent deletions at thePPE71–38locus, most notably in hypervirulent L2 Beijing strains. Here, we show that loss of thePPE71– 38locus causes increased stress response gene expression and increased triglyceride levels. In addition, we demonstrate that re-introduction ofPPE71into the L2 strain HN878 suppresses the baseline elevation of these transcripts, while overexpression ofPPE71increases the localization of PE_PGRS proteins and lipoproteins to theM.tbouter mycomembrane. Mouse infection confirmed the hypervirulence of thePPE71–38deletion strain and conversely showed thatPPE71overexpression attenuatesM.tb. Our results indicate that loss ofPPE71–38is sufficient to drive an adaptive transcriptional response seen inM.tbL2 strains that likely contributes to the hypervirulence of this lineage.