Complement system and pathogenicity of Leptospires: mechanisms of activation and evasion, identification of bacterial ligands, characterization of proteases and establishment of an in vivo murine model

• Grant number: 10/50043-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: June 01, 2010
• End date: July 31, 2015
• Field of knowledge: Biological Sciences - Immunology - Immunochemistry
• Principal Investigator: Lourdes Isaac
• Grantee: Lourdes Isaac
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Pesquisadores principais: Angela Silva Barbosa
• Associated scholarship(s): 11/15733-8 - Role of complement component C5 to in vivo leptospirose control in murine models, BP.MS

Abstract

Leptospirosis is one of the most important worldwide zoonoses and is caused by Leptospira. These bacteria are spread mostly through the urine from contaminated rodents. The immune response is essential for host protection and the activation of the complement system is important for bacteria killing. The characterization of how pathogens evade complement attack is a developing field of great relevance. Recently, it has been demonstrated that nonpathogenic Leptospira strains are rapidly killed by the complement system, whereas pathogenic strains are able to resist serum bactericidal activity. However, limited knowledge is available concerning the mechanisms employed by these bacteria to circumvent this major line of defense. In order to improve our understanding of the interactions between Leptospira and the host complement system, four main questions will be addressed in this project: 1) Do pathogenic and nonpathogenic leptospiral strains interact differentially with properdin, the positive regulator of the alternative pathway of complement activation? 2) Pathogenic Leptospira strains acquire host's negative complement regulators C4b-Binding Protein and Factor H. What are the bacterial ligands (surface molecules) involved in these interactions? 3) Do pathogenic Leptospira spp. employ other strategies to evade complement attack? Do they produce proteases capable of degrading crucial complement components? 4) Is the complement system capable of controlling infection by Leptospira? To address this particular question, an in vivo murine model will be established. We believe that a better comprehension of these processes will be useful for the development of new therapeutic strategies for the treatment of leptospirosis. (AU)

Scientific publications

(17)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DA SILVA, LUDMILA BEZERRA; MIRAGAIA, LIDIA DOS SANTOS; DANTAS BREDA, LEANDRO CARVALHO; ABE, CECILIA MARI; BRAGA SCHMIDT, MARIANA COSTA; MORO, ANA MARIA; MONARIS, DENIZE; CONDE, JONAS NASCIMENTO; JOZSI, MIHALY; ISAAC, LOURDES; et al. Pathogenic Leptospira Species Acquire Factor H and Vitronectin via the Surface Protein LcpA. Infection and Immunity, v. 83, n. 3, p. 888-897, MAR 2015. (11/07297-3, 10/50043-0)

FRAGA, TATIANA RODRIGUES; ISAAC, LOURDES; BARBOSA, ANGELA SILVA. Complement Evasion by Pathogenic Leptospira. FRONTIERS IN IMMUNOLOGY, v. 7, DEC 21 2016. (14/00926-3, 10/50043-0)

SILVA, ALDACILENE SOUZA; CASTIBLANCO VALENCIA, MONICA MARCELA; CIANCIARULLO, AURORA MARQUES; VASCONCELLOS, SILVIO ARRUDA; BARBOSA, ANGELA SILVA; ISAAC, LOURDES. Interaction of human complement factor H variants Tyr(402) and His(402) with Leptospira spp.. FRONTIERS IN IMMUNOLOGY, v. 2, 2011. (10/50043-0, 09/05979-0)

SALAZAR, NATALIA; CASTIBLANCO-VALENCIA, MONICA MARCELA; DA SILVA, LUDMILA BEZERRA; DE CASTRO, IRIS ARANTES; MONARIS, DENIZE; MASUDA, HANA PAULA; BARBOSA, ANGELA SILVA; MATTOS AREAS, ANA PAULA. Staphylococcus aureus Manganese Transport Protein C (MntC) Is an Extracellular Matrix- and Plasminogen-Binding Protein. PLoS One, v. 9, n. 11, NOV 19 2014. (11/07297-3, 10/50043-0)

CASTIBLANCO-VALENCIA, MONICA MARCELA; FRAGA, TATIANA RODRIGUES; DA SILVA, LUDMILA BEZERRA; MONARIS, DENIZE; ESTIMA ABREU, PATRICIA ANTONIA; STROBEL, STEFANIE; JOZSI, MIHALY; ISAAC, LOURDES; BARBOSA, ANGELA SILVA. Leptospiral Immunoglobulin-like Proteins Interact With Human Complement Regulators Factor H, FHL-1, FHR-1, and C4BP. Journal of Infectious Diseases, v. 205, n. 6, p. 995-1004, MAR 15 2012. (10/50043-0)

ABREU, AFONSO G.; FRAGA, TATIANA R.; GRANADOS MARTINEZ, ADRIANA P.; KONDO, MARCIA Y.; JULIANO, MARIA A.; JULIANO, LUIZ; NAVARRO-GARCIA, FERNANDO; ISAAC, LOURDES; BARBOSA, ANGELA S.; ELIAS, WALDIR P.. The Serine Protease Pic From Enteroaggregative Escherichia coli Mediates Immune Evasion by the Direct Cleavage of Complement Proteins. Journal of Infectious Diseases, v. 212, n. 1, p. 106-115, JUL 1 2015. (12/50191-4, 11/14103-0, 10/50043-0)

DE CASTRO, IRIS A.; BAVIA, LORENA; FRAGA, TATIANA R.; AMANO, MARIANE T.; BREDA, LEANDRO C. D.; GRANADOS-MARTINEZ, ADRIANA P.; DA SILVA, ANA M. G.; VASCONCELLOS, SILVIO A.; ISAAC, LOURDES. Role of Murine Complement Component C5 in Acute in Vivo Infection by Pathogenic Leptospira interrogans. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 8, MAR 8 2018. (15/09972-0, 10/50043-0)

CASTIBLANCO-VALENCIA, MONICA MARCELA; FRAGA, TATIANA RODRIGUES; PAGOTTO, ANA HELENA; DE TOLEDO SERRANO, SOLANGE MARIA; ESTIMA ABREU, PATRICIA ANTONIA; BARBOSA, ANGELA SILVA; ISAAC, LOURDES. 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. Immunobiology, v. 221, n. 5, p. 679-689, MAY 2016. (13/07467-1, 10/50043-0)

MACEDO, ANA CATARINA LUNZ; LORES, LAZARA ELENA SANTISTEBAN; ALBUQUERQUE, JOSE ANTONIO TAVARES; DUARTE, NILO JOSE COELHO; ROMANO, PASCHOALINA; EBNER, PERSIO ALMEIDA REZENDE; REZENDE, VINICIUS MARCONDES; SILVA, CLOVIS A. A.; ANDRADE, LUIS EDUARDO COELHO; VASCONCELOS, DEWTON MORAES; et al. A rare association between factor H deficiency and lupus: Case report and experimental treatment with curcumin. FRONTIERS IN PEDIATRICS, v. 10, p. 8-pg., 2022-11-04. (17/12924-3, 10/50043-0)

BAVIA, LORENA; DE CASTRO, IRIS A.; AMANO, MARIANE TAMI; GONCALVES DA SILVA, ANA MARIA; VASCONCELLOS, SILVIO ARRUDA; ISAAC, LOURDES. Cytokine Profile in Early Infection by Leptospira interrogans in A/J Mice. JOURNAL OF IMMUNOLOGY RESEARCH, v. 2019, OCT 7 2019. (11/15733-8, 10/50043-0)

CASTIBLANCO-VALENCIA, MONICA M.; FRAGA, TATIANA R.; BREDA, LEANDRO C. D.; VASCONCELLOS, SILVIO A.; FIGUEIRA, CLAUDIO P.; PICARDEAU, MATHIEU; WUNDER, ELSIO; KO, ALBERT I.; BARBOSA, ANGELA S.; ISAAC, LOURDES. Acquisition of negative complement regulators by the saprophyte Leptospira biflexa expressing LigA or LigB confers enhanced survival in human serum. Immunology Letters, v. 173, p. 61-68, MAY 2016. (15/09972-0, 10/50043-0)

BREDA, LEANDRO C. D.; HSIEH, CHING-LIN; CASTIBLANCO VALENCIA, MONICA M.; DA SILVA, LUDMILA B.; BARBOSA, ANGELA S.; BLOM, ANNA M.; YUNG-FU, CHANG; ISAAC, LOURDES. Fine Mapping of the Interaction between C4b-Binding Protein and Outer Membrane Proteins LigA and LigB of Pathogenic Leptospira interrogans. PLoS Neglected Tropical Diseases, v. 9, n. 10, OCT 2015. (11/14347-7, 10/50043-0)

SAHAGUN-RUIZ, ALFREDO; GRANADOS MARTINEZ, ADRIANA PATRICIA; DANTAS BREDA, LEANDRO CARVALHO; FRAGA, TATIANA RODRIGUES; CASTIBLANCO VALENCIA, MONICA MARCELA; BARBOSA, ANGELA SILVA; ISAAC, LOURDES. Pasteurella pneumotropica Evades the Human Complement System by Acquisition of the Complement Regulators Factor H and C4BP. PLoS One, v. 9, n. 10, OCT 27 2014. (10/50043-0)

SAHAGUN-RUIZ, ALFREDO; DANTAS BREDA, LEANDRO CARVALHO; CASTIBLANCO VALENCIA, MONICA MARCELA; ELIAS, WALDIR P.; MUNTHE-FOG, LEA; GARRED, PETER; BARBOSA, ANGELA SILVA; ISAAC, LOURDES. Studies of the binding of ficolin-2 and ficolin-3 from the complement lectin pathway to Leptospira biflexa, Pasteurella pneumotropica and Diarrheagenic Escherichia coli. Immunobiology, v. 220, n. 10, p. 1177-1185, OCT 2015. (10/50043-0)

DA SILVA, KARINA RIBEIRO; FRAGA, TATIANA RODRIGUES; LUCATELLI, JULIANA FAGGION; GRUMACH, ANETE SEVCIOVIC; ISAAC, LOURDES. Skipping of exon 27 in C3 gene compromises TED domain and results in complete human C3 deficiency. Immunobiology, v. 221, n. 5, p. 641-649, MAY 2016. (10/50043-0)

WOLFF, DANIELLY G.; CASTIBLANCO-VALENCIA, MONICA M.; ABE, CECILIA M.; MONARIS, DENIZE; MORAIS, ZENAIDE M.; SOUZA, GISELE O.; VASCONCELLOS, SILVIO A.; ISAAC, LOURDES; ABREU, PATRICIA A. E.; BARBOSA, ANGELA S.. Interaction of Leptospira Elongation Factor Tu with Plasminogen and Complement Factor H: A Metabolic Leptospiral Protein with Moonlighting Activities. PLoS One, v. 8, n. 11, NOV 27 2013. (11/07297-3, 10/50043-0)

FRAGA, TATIANA RODRIGUES; COURROL, DANIELLA DOS SANTOS; CASTIBLANCO-VALENCIA, MONICA MARCELA; HIRATA, IZAURA YOSHICO; VASCONCELLOS, SLVIO ARRUDA; JULIANO, LUIZ; BARBOSA, ANGELA SILVA; ISAAC, LOURDES. Immune Evasion by Pathogenic Leptospira Strains: The Secretion of Proteases that Directly Cleave Complement Proteins. Journal of Infectious Diseases, v. 209, n. 6, p. 876-886, MAR 15 2014. (10/50043-0)