title: A Brucella spp. Protease Inhibitor Limits Antigen Lysosomal Proteolysis, Increases Cross-Presentation, and Enhances CD8+ T Cell Responses.
abstract: In this study, we demonstrate that the unlipidated (U) outer membrane protein (Omp) 19 from Brucella spp. is a competitive inhibitor of human cathepsin L. U-Omp19 inhibits lysosome cathepsins and APC-derived microsome activity in vitro and partially inhibits lysosomal cathepsin L activity within live APCs. Codelivery of U-Omp19 with the Ag can reduce intracellular Ag digestion and increases Ag half-life in dendritic cells (DCs). U-Omp19 retains the Ag in Lamp-2(+) compartments after its internalization and promotes a sustained expression of MHC class I/peptide complexes in the cell surface of DCs. Consequently, U-Omp19 enhances Ag cross-presentation by DCs to CD8(+) T cells. U-Omp19 s.c. delivery induces the recruitment of CD11c(+)CD8α(+) DCs and monocytes to lymph nodes whereas it partially limits in vivo Ag proteolysis inside DCs. Accordingly, this protein is able to induce CD8(+) T cell responses in vivo against codelivered Ag. Antitumor responses were elicited after U-Omp19 coadministration, increasing survival of mice in a murine melanoma challenge model. Collectively, these results indicate that a cysteine protease inhibitor from bacterial origin could be a suitable component of vaccine formulations against tumors.
authors.affiliation: Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martín, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, 1650 Buenos Aires, Argentina;
authors.forename: Lorena M
authors.initials: LM
authors.lastname: Coria
authors.affiliation: Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martín, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, 1650 Buenos Aires, Argentina;
authors.forename: Andrés E
authors.initials: AE
authors.lastname: Ibañez
authors.affiliation: Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, 1428 Buenos Aires, Argentina;
authors.forename: Mercedes
authors.initials: M
authors.lastname: Tkach
authors.affiliation: Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Academia Nacional de Medicina, 1425 Buenos Aires, Argentina;
authors.forename: Florencia
authors.identifier: 0000-0002-9220-2210
authors.initials: F
authors.lastname: Sabbione
authors.affiliation: Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martín, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, 1650 Buenos Aires, Argentina;
authors.forename: Laura
authors.initials: L
authors.lastname: Bruno
authors.affiliation: Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martín, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, 1650 Buenos Aires, Argentina;
authors.forename: Marianela V
authors.initials: MV
authors.lastname: Carabajal
authors.affiliation: Fundación Instituto Leloir, Instituto de Investigaciones Bioquímicas de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, 1405 Buenos Aires, Argentina; and.
authors.forename: Paula M
authors.identifier: 0000-0001-6944-7896
authors.initials: PM
authors.lastname: Berguer
authors.affiliation: Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Academia Nacional de Medicina, 1425 Buenos Aires, Argentina;
authors.forename: Paula
authors.initials: P
authors.lastname: Barrionuevo
authors.affiliation: Laboratorio de Mecanismos Moleculares de Carcinogénesis, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, 1428 Buenos Aires, Argentina;
authors.forename: Roxana
authors.identifier: 0000-0002-7776-3378
authors.initials: R
authors.lastname: Schillaci
authors.affiliation: Instituto de Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Academia Nacional de Medicina, 1425 Buenos Aires, Argentina;
authors.forename: Analía S
authors.identifier: 0000-0001-7254-1082
authors.initials: AS
authors.lastname: Trevani
authors.affiliation: Instituto de Inmunología, Genética y Metabolismo, Laboratorio de Inmunogenética, Hospital de Clínicas "José de San Martín," Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Universidad de Buenos Aires, 1120 Buenos Aires, Argentina.
authors.forename: Guillermo H
authors.initials: GH
authors.lastname: Giambartolomei
authors.affiliation: Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martín, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, 1650 Buenos Aires, Argentina;
authors.forename: Karina A
authors.identifier: 0000-0003-4448-0977
authors.initials: KA
authors.lastname: Pasquevich
authors.affiliation: Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, Universidad Nacional de San Martín, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, 1650 Buenos Aires, Argentina; jucassataro@iibintech.com.ar.
authors.forename: Juliana
authors.initials: J
authors.lastname: Cassataro
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000276:immunology; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism*; D002002:Brucella / Q000276:immunology*; D002006:Brucellosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D019496:Cancer Vaccines / Q000276:immunology*; D002403:Cathepsins / Q000378:metabolism*; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D008074:Lipoproteins / Q000378:metabolism*; D008213:Lymphocyte Activation; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D000942:Antigens, Bacterial; D000951:Antigens, Neoplasm; D001425:Bacterial Outer Membrane Proteins; D019496:Cancer Vaccines; D008074:Lipoproteins; D052119:Lysosomal-Associated Membrane Protein 2; C097319:OMP19 protein, Brucella abortus; D002403:Cathepsins