title: Strong immunogenicity and cross-reactivity of Mycobacterium tuberculosis ESX-5 type VII secretion: encoded PE-PPE proteins predicts vaccine potential.
abstract: The 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 EccD(5), 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.
authors.affiliation: Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France.
authors.forename: Fadel
authors.initials: F
authors.lastname: Sayes
authors.forename: Lin
authors.initials: L
authors.lastname: Sun
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Di Luca
authors.forename: Roxane
authors.initials: R
authors.lastname: Simeone
authors.forename: Nathalie
authors.initials: N
authors.lastname: Degaiffier
authors.forename: Laurence
authors.initials: L
authors.lastname: Fiette
authors.forename: Semih
authors.initials: S
authors.lastname: Esin
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.forename: Daria
authors.initials: D
authors.lastname: Bottai
authors.forename: Claude
authors.initials: C
authors.lastname: Leclerc
authors.forename: Laleh
authors.initials: L
authors.lastname: Majlessi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000940:Antigenic Variation; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D058947:Bacterial Secretion Systems; D003429:Cross Reactions; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D021381:Protein Transport; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology*; D032581:Tuberculosis Vaccines / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; D032581:Tuberculosis Vaccines