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.
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November 2013
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Research Article|
October 10 2013
Mining the bacterial unknown proteome: identification and characterization of a novel family of highly conserved protective antigens in Staphylococcus aureus
Christina Schluepen;
Christina Schluepen
1
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Enrico Malito;
Enrico Malito
1
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
†Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, U.S.A.
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Ambra Marongiu;
Ambra Marongiu
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Markus Schirle;
Markus Schirle
‡Novartis Institute for Biomedical Research, Cambridge, MA 02139, U.S.A.
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Elisabeth McWhinnie;
Elisabeth McWhinnie
‡Novartis Institute for Biomedical Research, Cambridge, MA 02139, U.S.A.
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Paola Lo Surdo;
Paola Lo Surdo
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Marco Biancucci;
Marco Biancucci
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Fabiana Falugi;
Fabiana Falugi
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Vincenzo Nardi-Dei;
Vincenzo Nardi-Dei
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Sara Marchi;
Sara Marchi
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Maria Rita Fontana;
Maria Rita Fontana
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Benedetta Lombardi;
Benedetta Lombardi
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Maria Grazia De Falco;
Maria Grazia De Falco
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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C. Daniela Rinaudo;
C. Daniela Rinaudo
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Glen Spraggon;
Glen Spraggon
†Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, U.S.A.
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Mikkel Nissum;
Mikkel Nissum
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Fabio Bagnoli;
Fabio Bagnoli
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Guido Grandi;
Guido Grandi
2
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
2To whom correspondence should be addressed (email guido.grandi@novartis.com).
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Matthew J. Bottomley;
Matthew J. Bottomley
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Sabrina Liberatori
Sabrina Liberatori
*Research Department, Novartis Vaccines and Diagnostics, 53100 Siena, Italy
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Publisher: Portland Press Ltd
Received:
April 16 2013
Revision Received:
July 23 2013
Accepted:
July 29 2013
Accepted Manuscript online:
July 29 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 455 (3): 273–284.
Article history
Received:
April 16 2013
Revision Received:
July 23 2013
Accepted:
July 29 2013
Accepted Manuscript online:
July 29 2013
Citation
Christina Schluepen, Enrico Malito, Ambra Marongiu, Markus Schirle, Elisabeth McWhinnie, Paola Lo Surdo, Marco Biancucci, Fabiana Falugi, Vincenzo Nardi-Dei, Sara Marchi, Maria Rita Fontana, Benedetta Lombardi, Maria Grazia De Falco, C. Daniela Rinaudo, Glen Spraggon, Mikkel Nissum, Fabio Bagnoli, Guido Grandi, Matthew J. Bottomley, Sabrina Liberatori; Mining the bacterial unknown proteome: identification and characterization of a novel family of highly conserved protective antigens in Staphylococcus aureus. Biochem J 1 November 2013; 455 (3): 273–284. doi: https://doi.org/10.1042/BJ20130540
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