Strong Immunogenicity and Cross-Reactivity of Mycobacterium tuberculosis ESX-5 Type VII Secretion -Encoded PE-PPE Proteins Predicts Vaccine Potential

SummaryThe genome of Mycobacterium tuberculosis (Mtb) encodes five type VII secretion systems, ESX-1 to ESX-5, most of which are associated with genes encoding PE/PPE proteins, named after their N-terminal Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs. Here, we describe the strong T cell immunogenicity of the ESX-5-encoded PE/PPE proteins, which share a large panel of cross-reactive CD4+ epitopes with substantial numbers of their ESX-5-nonassociated PE/PPE homologs. The immunogenicity of these numerous PE/PPE proteins is dependent on their export by a functional EccD5, the predicted transmembrane channel of the ESX-5 secretion apparatus. The Mtb Δppe25-pe19 mutant deleted for all ESX-5-associated pe and ppe genes, although highly attenuated in immunocompetent mice, remains able to induce immunity against the ESX-5-associated PE/PPE virulence factors, via cross-reactivity with their numerous homologs, and against the ESX-1 virulence factors ESAT-6/CFP-10. The Δppe25-pe19 strain is strongly protective against Mtb infection in mice and represents a potential antituberculosis vaccine candidate.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (252 K)Download as PowerPoint slideHighlights► Mtb ESX-5-associated and -nonassociated PE/PPE proteins are highly immunogenic ► ESX-5 core component eccD5 modulates the mycobacterial antigenic repertoire ► ESX-5 PE/PPE deleted Δppe25-pe19 Mtb strain is avirulent, yet strongly immunogenic ► Δppe25-pe19 strain protects mice against Mtb infection and represents a vaccine candidate