PPE50 variants as novel phylogeographic signatures of host-pathogen co-evolution in tuberculosis.

While evidence supports co-evolution between Mycobacterium tuberculosis and humans, underlying mechanisms remain unclear. We identified PPE50 as a novel subfamily of PE/PPE proteins comprising eight variants. Surveying 387 M. tuberculosis complex (MTBC) strains representing global phylogeography, we found PPE50 variants are lineage-specific and stably associated with geographic regions, defining them as phylogeographically-associated proteins (PAPs). PPE50-381 is the ancestral variant (present in early-branching M. canettii) and the only variant observed in both Ancient and Modern MTBC lineages. Transcriptomic analysis confirmed that ppe50 variant genes are expressed in strains from respective MTBC lineages, but not in all L1 strains and sub-lineages L2.1 and L4.1 where the gene was deleted. In silico analysis revealed significant structural diversity among variants, particularly in C-terminal regions. This strong association of M. tuberculosis protein diversity with phylogeography suggests PPE50 may contribute to MTBC adaptation to different host populations. Further characterization of PPE50 and other PAPs may facilitate improved targeted diagnostics, therapeutics and vaccines.