Importantly, independent mouse vaccination models show that BCG::ESX-1<sup>Mmar</sup> confers superior protection relative to parental BCG against challenges with highly virulent M. tuberculosis.
PPE25 and PPE26, the Mycobacterium tuberculosis proline-proline-glutamic acid (PPE) family proteins, are members of the M. tuberculosisESX-5 system associated with virulence of M. tuberculosis.
Much current TB vaccine research focuses on engineering live mycobacteria to interfere with phagosome biology and host intracellular pathways including apoptosis and autophagy, with candidates such as BCG Δzmp1, BCG ΔureC::hly, BCG::ESX-1<sup>Mmar</sup>, Mtb ΔphoP ΔfadD26, Mtb ΔRD1 ΔpanCD and M. smegmatis Δesx-3::esx-3(Mtb) in the development pipeline.
High quality homoplastic single nucleotide polymorphisms were observed in genes known to confer drug resistance as well as genes in the Mycobacterium tuberculosisESX secreted protein pathway, pks12, and close to toxin/anti-toxin pairs.
Our work, reviewed here, has established that the phosphate sensing Pst/SenX3-RegX3 system directly activates ESX-5 secretion in response to phosphate limitation, a relevant environmental signal likely encountered by M. tuberculosis in the host.
In conclusion, the ESX-5a region is nonredundant with its ESX-5 paralog and is necessary for secretion of a specific subset of proteins in M. tuberculosis and M. marinum that are important for bacterial virulence of M. marinum.
To define the role of the ESX-5 system in M. tuberculosis, in this study, we have constructed five M. tuberculosis H37Rv ESX-5 knockout/deletion mutants, inactivating eccA(5), eccD(5), rv1794 and esxM genes or the ppe25-pe19 region.