title: Plasmin cleaves fibrinogen and the human complement proteins C3b and C5 in the presence of Leptospira interrogans proteins: A new role of LigA and LigB in invasion and complement immune evasion.
abstract: Plasminogen is a single-chain glycoprotein found in human plasma as the inactive precursor of plasmin. When converted to proteolytically active plasmin, plasmin(ogen) regulates both complement and coagulation cascades, thus representing an important target for pathogenic microorganisms. Leptospira interrogans binds plasminogen, which is converted to active plasmin. Leptospiral immunoglobulin-like (Lig) proteins are surface exposed molecules that interact with extracellular matrix components and complement regulators, including proteins of the FH family and C4BP. In this work, we demonstrate that these multifunctional molecules also bind plasminogen through both N- and C-terminal domains. These interactions are dependent on lysine residues and are affected by ionic strength. Competition assays suggest that plasminogen does not share binding sites with C4BP or FH on Lig proteins at physiological molar ratios. Plasminogen bound to Lig proteins is converted to proteolytic active plasmin in the presence of urokinase-type plasminogen activator (uPA). Lig-bound plasmin is able to cleave the physiological substrates fibrinogen and the complement proteins C3b and C5. Taken together, our data point to a new role of LigA and LigB in leptospiral invasion and complement immune evasion. Plasmin(ogen) acquisition by these versatile proteins may contribute to Leptospira infection, favoring bacterial survival and dissemination inside the host.
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Mónica Marcela
authors.initials: MM
authors.lastname: Castiblanco-Valencia
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Tatiana Rodrigues
authors.initials: TR
authors.lastname: Fraga
authors.affiliation: Special Laboratory of Applied Toxinology, Center of Toxins, Immune-Response and Cell Signaling (CeTICS), Butantan Institute, São Paulo, Brazil.
authors.forename: Ana Helena
authors.initials: AH
authors.lastname: Pagotto
authors.affiliation: Special Laboratory of Applied Toxinology, Center of Toxins, Immune-Response and Cell Signaling (CeTICS), Butantan Institute, São Paulo, Brazil.
authors.forename: Solange Maria de Toledo
authors.initials: SM
authors.lastname: Serrano
authors.affiliation: Laboratory of Bacteriology, Butantan Institute, São Paulo, Brazil.
authors.forename: Patricia Antonia Estima
authors.initials: PA
authors.lastname: Abreu
authors.affiliation: Laboratory of Bacteriology, Butantan Institute, São Paulo, Brazil.
authors.forename: Angela Silva
authors.initials: AS
authors.lastname: Barbosa
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: louisaac@icb.usp.br.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Isaac
mesh_terms: D000942:Antigens, Bacterial / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology*; D001665:Binding Sites; D003179:Complement C3b / Q000276:immunology* / Q000378:metabolism; D050716:Complement C4b-Binding Protein / Q000378:metabolism; D003182:Complement C5 / Q000276:immunology* / Q000378:metabolism; D004789:Enzyme Activation; D005340:Fibrinogen / Q000378:metabolism*; D005341:Fibrinolysin / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D007921:Leptospira interrogans / Q000276:immunology; D007922:Leptospirosis / Q000276:immunology / Q000378:metabolism; D009994:Osmolar Concentration; D011485:Protein Binding; D059748:Proteolysis
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C055609:C4BPA protein, human; D050716:Complement C4b-Binding Protein; D003182:Complement C5; D003179:Complement C3b; D005340:Fibrinogen; D005341:Fibrinolysin
keywords: Complement; Immune evasion; Leptospira; Lig proteins; Plasminogen