title: Mining the bacterial unknown proteome: identification and characterization of a novel family of highly conserved protective antigens in Staphylococcus aureus.
abstract: In the human pathogen Staphylococcus aureus, there exists an enormous diversity of proteins containing DUFs (domains of unknown function). In the present study, we characterized the family of conserved staphylococcal antigens (Csa) classified as DUF576 and taxonomically restricted to Staphylococci. The 18 Csa paralogues in S. aureus Newman are highly similar at the sequence level, yet were found to be expressed in multiple cellular locations. Extracellular Csa1A was shown to be post-translationally processed and released. Molecular interaction studies revealed that Csa1A interacts with other Csa paralogues, suggesting that these proteins are involved in the same cellular process. The structures of Csa1A and Csa1B were determined by X-ray crystallography, unveiling a peculiar structure with limited structural similarity to other known proteins. Our results provide the first detailed biological characterization of this family and confirm the uniqueness of this family also at the structural level. We also provide evidence that Csa family members elicit protective immunity in in vivo animal models of staphylococcal infections, indicating a possible important role for these proteins in S. aureus biology and pathogenesis. These findings identify the Csa family as new potential vaccine candidates, and underline the importance of mining the bacterial unknown proteome to identify new targets for preventive vaccines.
authors.affiliation: *Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy.
authors.forename: Christina
authors.initials: C
authors.lastname: Schluepen
authors.forename: Enrico
authors.initials: E
authors.lastname: Malito
authors.forename: Ambra
authors.initials: A
authors.lastname: Marongiu
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.forename: Elisabeth
authors.initials: E
authors.lastname: McWhinnie
authors.forename: Paola
authors.initials: P
authors.lastname: Lo Surdo
authors.forename: Marco
authors.initials: M
authors.lastname: Biancucci
authors.forename: Fabiana
authors.initials: F
authors.lastname: Falugi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Nardi-Dei
authors.forename: Sara
authors.initials: S
authors.lastname: Marchi
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Fontana
authors.forename: Benedetta
authors.initials: B
authors.lastname: Lombardi
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: De Falco
authors.forename: C Daniela
authors.initials: CD
authors.lastname: Rinaudo
authors.forename: Glen
authors.initials: G
authors.lastname: Spraggon
authors.forename: Mikkel
authors.initials: M
authors.lastname: Nissum
authors.forename: Fabio
authors.initials: F
authors.lastname: Bagnoli
authors.forename: Guido
authors.initials: G
authors.lastname: Grandi
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bottomley
authors.forename: Sabrina
authors.initials: S
authors.lastname: Liberatori
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D018360:Crystallography, X-Ray; D057225:Data Mining; D051379:Mice; D008815:Mice, Inbred Strains; D020543:Proteome / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013203:Staphylococcal Infections / Q000276:immunology / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D020543:Proteome