Loss of the <i>PPE71-esxX-esxY-PPE38</i> locus drives adaptive transcriptional responses and hypervirulence of <i>Mycobacterium tuberculosis</i> lineage 2.

Abstract

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