Loss of the PPE71-esxX-esxY-PPE38 locus drives adaptive transcriptional responses and hypervirulence of Mycobacterium tuberculosis Lineage 2

Mycobacterium tuberculosis ( M.tb ) is remarkable for its immense global disease burden and low mutation rate. Despite strong selective pressure, M.tb shows frequent deletions at the PPE71–38 locus, most notably in hypervirulent L2 Beijing strains. Here, we show that loss of the PPE71– 38 locus causes increased stress response gene expression and increased triglyceride levels. In addition, we demonstrate that re-introduction of PPE71 into the L2 strain HN878 suppresses the baseline elevation of these transcripts, while overexpression of PPE71 increases the localization of PE_PGRS proteins and lipoproteins to the M.tb outer mycomembrane. Mouse infection confirmed the hypervirulence of the PPE71–38 deletion strain and conversely showed that PPE71 overexpression attenuates M.tb . Our results indicate that loss of PPE71–38 is sufficient to drive an adaptive transcriptional response seen in M.tb L2 strains that likely contributes to the hypervirulence of this lineage.