Etiopathogenesis of Leptospirosis: contribution of the complement system for the control of infection in vivo and in vitro and inflammatory response: identification of gene polymorphisms of the complement system in Leptospirosis patients

• Grant number: 17/12924-3
• Support Opportunities: Research Projects - Thematic Grants
• Start date: April 01, 2018
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Immunology - Immunogenetics
• 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 researchers: Federico Costa ; Ligia Ely Morganti Ferreira Dias ; Lorena Bavia ; Ricardo Ruiz Mazzon ; Rosa Maria Chura Chambi
• Associated scholarship(s): 24/16836-5 - Use of metalloproteinases thermolysin and leptolysin, and LigA as vaccine candidates against experimental leptospirosis., BP.PD; 23/11462-7 - Proteolytic profile of six strains of Leptospira on complement system and extracellular matrix molecules: comparison and correlation with symptoms and infection damage., BP.TT; 23/05216-3 - Experimental vaccine against leptospirosis: evaluation of the leptolysin metalloprotease from leptospires as a vaccine antigen, BP.TT; + associated scholarships 22/06743-4 - Evaluation of leptolysin metalloprotease as a vaccine candidate against leptospirosis, BP.TT; 19/19800-3 - Training in microbiology and immunology techniques, BP.TT; 18/12189-4 - Scientific Dissemination about Leptospirosis in the media, BP.JC - associated scholarships

Abstract

Leptospirosis is one of the most important zoonosis worldwide, affecting especially underdeveloped countries with mild and tropical temperatures. Leptospirosis is considered a neglected disease and the immune mechanisms responsible for its control are not well known. The complement system is important for Leptospire killing and pathogenic species use a variety of strategies to evade this system, thereby allowing them to disseminate in the host for longer periods of time. A detailed understanding of how pathogenic Leptospires escape the complement system is an important challenge in biomedical sciences. In this thematic project, we plan to explore in more detail a number of questions regarding the mechanisms of immune evasion by Leptospires. Specifically, we plan to investigate: 1) the role of C3 in the control of Leptospirosis, both in vivo and in vitro, and in the etiopathogenesis responsible for the acute and chronic lesions in the liver and kidneys of infected animals; 2) what are the complement activation pathways involved in Leptospire killing; 3) how are thermolysins, metalloproteases secreted by pathogenic Leptospires, regulated and activated and what are the consequences of heterologous expression of these proteases by a non-pathogenic Leptospira species and, 4) correlations between the polymorphism of certain complement genes and disease severity in Leptospirosis patients. Detailed investigation of the complement activation pathways involved in Leptospira killing and mechanisms of phagocytosis evasion by pathogenic Leptospires will shed light on unresolved questions regarding Leptospira pathogenesis. In addition, the development of new genetic tools will allow us to genetically manipulate Leptospires in order to test hypothesis related to the functions of specific genes and the identification and characterization of specific Leptospira virulence factors. (AU)

Scientific publications

(14)

(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)

BARBOSA, ANGELA SILVA; ISAAC, LOURDES. Strategies used byLeptospiraspirochetes to evade the host complement system. FEBS Letters, v. 594, n. 16, SI, p. 2633-2644, AUG 2020. (18/12896-2, 17/12924-3)

BARBOSA, ANGELA SILVA; ISAAC, LOURDES. Strategies used by Leptospira spirochetes to evade the host complement system. FEBS Letters, v. 594, n. 16, p. 12-pg., 2020-03-24. (18/12896-2, 17/12924-3)

DA SILVA, TIAGO FRANCISCO; AMAMURA, THAIS AKEMI; VALADAO, IURI CORDEIRO; CARNEIRO, MILENA CARVALHO; FREITAS, VANESSA MORAIS; LEPIQUE, ANA PAULA; ISAAC, LOURDES. Complement system component 3 deficiency modulates the phenotypic profile of murine macrophages. Cellular Immunology, v. 405, p. 10-pg., 2024-10-28. (19/01435-7, 17/12924-3)

SANTIESTEBAN-LORES, LAZARA ELENA; CARNEIRO, MILENA CARVALHO; ISAAC, LOURDES; BAVIA, LORENA. Complement System in Alcohol-Associated Liver Disease. Immunology Letters, v. 236, p. 37-50, AUG 2021. (17/12924-3, 19/19800-3, 07/03393-2)

BARBOSA, ANGELA SILVA; ISAAC, LOURDES. Strategies used byLeptospiraspirochetes to evade the host complement system. FEBS Letters, MAR 2020. (17/12924-3, 18/12896-2)

MARTINEZ, ADRIANA PATRICIA GRANADOS; ABREU, PATRICIA ANTONIA ESTIMA; DE ARRUDA VASCONCELLOS, SILVIO; HO, PAULO LEE; FERREIRA, VIVIANA P.; SAGGU, GURPANNA; BARBOSA, ANGELA SILVA; ISAAC, LOURDES. The Role of Properdin in Killing of Non-Pathogenic Leptospira biflexa. FRONTIERS IN IMMUNOLOGY, v. 11, NOV 10 2020. (17/12924-3)

OKOCHI ALVES DA SILVA, PRISCILLA YURI; MIDON, LEONARDO MOURA; HEINEMANN, MARCOS BRYAN; VASCONCELOS, DEWTON DE MORAES; BARBOSA, ANGELA SILVA; ISAAC, LOURDES. Contribution of Complement System pathways to the killing of Leptospira spp.. Microbes and Infection, v. 22, n. 10, p. 550-557, NOV-DEC 2020. (17/12924-3, 17/18936-3)

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)

SANTIESTEBAN-LORES, LAZARA ELENA; AMAMURA, THAIS AKEMI; DA SILVA, TIAGO FRANCISCO; MIDON, LEONARDO MOURA; CARNEIRO, MILENA CARVALHO; ISAAC, LOURDES; BAVIA, LORENA. A double edged-sword - The Complement System during SARS-CoV-2 infection. Life Sciences, v. 272, MAY 1 2021. (19/19800-3, 17/10208-9, 17/12924-3, 18/26574-7, 19/01435-7)

AZEVEDO, ISABELA RESENDE; AMAMURA, THAIS AKEMI; ISAAC, LOURDES. Human leptospirosis: In search for a better vaccine. Scandinavian Journal of Immunology, v. 98, n. 5, p. 21-pg., 2023-08-07. (20/16104-3, 17/10208-9, 17/12924-3)

COURROL, DANIELLA DOS SANTOS; SANTOS, CASSIA MOREIRA; CHURA-CHAMBI, ROSA MARIA; MORGANTI, LIGIA; AVELAR, KATIA ELIANE SANTOS; MAIA, FERNANDA DE MORAES; RODRIGUES-DA-SILVA, RODRIGO NUNES; WUNDER, ELSIO AUGUSTO; BARBOSA, ANGELA SILVA. Leptospira Leptolysin Contributes to Serum Resistance but Is Not Essential for Acute Infection. Molecular Microbiology, v. 122, n. 5, p. 10-pg., 2024-11-01. (18/12896-2, 19/22706-9, 17/12924-3)

HECKTHEUER, AMANDA SILVA; SANTOS, CASSIA MOREIRA; FERREIRA, FABIENNE ANTUNES; BARBOSA, ANGELA SILVA; ISAAC, LOURDES; MARQUES, MARILIS VALLE; MAZZON, RICARDO RUIZ. The Leptospira interrogans proteome's response to zinc highlights the potential involvement of this metal in translational-machinery and virulence. BIOMETALS, v. N/A, p. 22-pg., 2024-09-21. (17/12924-3)

SANTIESTEBAN-LORES, LAZARA ELENA; MIDON, LEONARDO MOURA; FRANCO, THIRSAALVARES; DE OLIVEIRA, LUCIANO MARCONDES; HIBI, SUMIRE; CHIANI, YOSENA; MENESES, GDAYLLONCAVALCANTE; DAHER, ELIZABETH DE FRANCESCO; FONSECA, DENISE MORAES; PONTILLO, ALESSANDRA; et al. Analysis of Complement Factor H gene polymorphisms and their association with clinical manifestations ofleptospirosis. IMMUNOGENETICS, v. 77, n. 1, p. 11-pg., 2025-12-01. (17/12924-3)

COURROL, DANIELLA DOS SANTOS; DA SILVA, CRISTIANE CASTILHO FERNANDES; PRADO, LUAN GAVIAO; CHURA-CHAMBI, ROSA MARIA; MORGANTI, LIGIA; DE SOUZA, GISELE OLIVEIRA; HEINEMANN, MARCOS BRYAN; ISAAC, LOURDES; CONTE, FERNANDO PAIVA; VIEIRA PORTARO, FERNANDA CALHETA; et al. Leptolysin, a Leptospira secreted metalloprotease of the pappalysin family with broad-spectrum activity. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 12, p. 20-pg., 2022-08-23. (18/12896-2, 19/22706-9, 17/12924-3)