Título: Professora Associada, Livre-Docente

Laboratório: Laboratório de Complemento
Telefone: +55 (11) 3091 7390
E-mail: louisaac@icb.usp.br

Lattes

A leptospirose é uma das principais zoonoses no mundo todo, sendo mais frequentemente encontrada em países de clima tropical e sub-tropical, especialmente em regiões com saneamento insatisfatório. Trata-se de uma doença com mais de um milhão de casos novos a cada ano, sendo fatal em 5-10% deles.

Leptospiras patogênicas são bastante resistentes à ação do Sistema Complemento, enquanto leptospiras não patogênicas morrem rapidamente. Investigamos os mecanismos pelos quais estas bactérias são capazes de driblar este sistema, quais proteínas bacterianas estão envolvidas com esta evasão e interações entre proteínas do Sistema Complemento com proteínas de leptospiras. Paralelamente, desenvolvemos também modelos experimentais onde candidatos vacinais vêm sendo testados, com o intuito de propor medidas profiláticas mais eficientes para o controle desta zoonose.

Leptospirosis is one of the main zoonosis worldwide, being more frequently in countries with tropical and sub-tropical climates, especially in regions with poor sanitation. It is a disease with more than one million new cases each year, being fatal in 5-10% of them.

Pathogenic leptospires are quite resistant to the Complement System activation, while non-pathogenic leptospires are quite susceptible. We investigate the mechanisms by which these bacteria are able to escape this system, which bacterial proteins are involved in this evasion and interactions between the Complement System and leptospiral proteins. In addition, we are also interested in experimental vaccine models, in order to suggest efficient immunoprophylaxy to control this zoonosis.

Linha de Pesquisa

1. Imunodeficiências de Proteínas do Sistema Complemento Humano.
2. Mecanismos de Escape do Sistema Complemento por Leptospiras Patogênicas

Resumo

1. O Laboratório de Complemento tem por interesse estudar imunodeficiências raras de proteínas do sistema complemento humano. Estas deficiências são responsáveis pela alta susceptibilidade dos pacientes deficientes a infecções graves e repetitivas e/ou doenças auto-imunes. Amostras de pacientes com suspeita de imuinodeficiência de complemento são caracterizadas imunologicamente e as bases genético-moleculares responsáveis por estas deficiências são investigadas.
2. eptospiras patogênicas são bastante resistentes à ação do sistema complemento, enquanto leptospiras não patogênicas morrem rapidamente em função da ativação deste sistema. Investigamos os mecanismos pelos quais estas bactérias são capazes de driblar este sistema, quais proteínas bacterianas estão envolvidas com esta evasão e interações entre proteínas do sistema complemento com proteínas de leptospiras.

Publicações Selecionadas/Selected Publications (2011-2021)

1. Santiesteban-Lores LE, Amamura TA, da Silva TF, Midon LM, Carneiro MC, Isaac L, Bavia L. (2021). A double edged-sword – The Complement System during SARS-CoV-2 infection. Life Sciences;272:119245. doi: 10.1016/j.lfs.2021.119245.
2. Santiesteban-Lores LE, Carneiro MC, Isaac L, Bavia L. (2021). Complement System in Alcohol-Associated Liver Disease. Immunology Letters;236:37-50. doi: 10.1016/j.imlet.2021.05.007.
3. Martinez APG, Abreu PAE, de Arruda Vasconcellos S, Ho PL, Ferreira VP, Saggu G, Barbosa AS and Isaac L (2020) The Role of Properdin in Killing of Non-Pathogenic Leptospira biflexa. Frontiers in Immunology;11:572562. doi: 10.3389/fimmu.2020.572562.
4. Alves da Silva PYO, Midon LM, Heinemann MB, de Moraes Vasconcelos D, Barbosa AS, Isaac L (2020) Contribution of Complement System Pathways to the Killing of Leptospira spp. Microbial Pathogenesis;S1286-4579(20)30143-X. doi/ 10.1016/j.micinf.2020.07.005.
5. Barbosa AS, Isaac L (2020) Strategies used by Leptospira spirochetes to evade the host complement system. FEBS Letters;10.1002/1873-3468.13768. doi:10.1002/1873-3468.13768.
6. Bavia L, de Castro ÍA, Amano MT, da Silva AMG, Vasconcellos SA, Isaac L. (2019) Cytokine Profile in Early Infection by Leptospira interrogans in A/J Mice. J Immunol Research 7;2019:1892508. doi: 10.1155/2019/1892508.
7. Moreno-Torres A, Malvido-Jiménez IR, de la Peña-Moctezuma A, Castillo Sánchez LO, Fraga TR, Barbosa AS, Isaac L, Sahagún-Ruiz A (2019) Culture-attenuated pathogenic Leptospira lose the ability to survive to complement-mediated-killing due to lower expression of factor H binding proteins. Microbes and Infection;21:377-385. doi:10.1016/j.micinf.2019.03.001.
8. de Castro ÍA, Bavia L, Fraga TR, Amano MT, Breda LCD, Granados-Martinez AP, da Silva AMG, Vasconcellos SA, Isaac L. (2018) Role of Murine Complement Component C5 in Acute in Vivo Infection by Pathogenic Leptospira interrogans. Frontiers in Cellular and Infectious Microbiology;8:63. doi: 10.3389/fcimb.2018.00063.
9. Chura-Chambi RM, Fraga TR, da Silva LB, Yamamoto BB, Isaac L, Barbosa AS, Morganti L. (2018) Leptospira interrogans thermolysin refolded at high pressure and alkaline pH displays proteolytic activity against complement C3. Biotechnology Reports (Amst);19:e00266. doi:10.1016/j.btre.2018.e00266.
10. da Silva LB, Menezes MC, Kitano ES, Oliveira AK, Abreu AG, Souza GO, Heinemann MB, Isaac L, Fraga TR, Serrano SMT, Barbosa AS (2018) Leptospira interrogans Secreted Proteases Degrade Extracellular Matrix and Plasma Proteins From the Host. Frontiers in Cellular and Infection Microbiology;8:92. doi:10.3389/fcimb.2018.00092.
11. Amamura TA, Fraga TR, Vasconcellos SA, Barbosa AS, Isaac L (2017) Pathogenic Leptospira Secreted Proteases Target the Membrane Attack Complex: A Potential Role for Thermolysin in Complement Inhibition. Frontiers in Microbiology;8:1-16. doi: 10.3389/fmicb.2017.00958.
12. Breda LCD, Vasconcellos SA, de Moraes Vasconcelos D, Isaac L. (2018) Binding of human complement C1 esterase inhibitor to Leptospira spp. Immunobiology;223(2):183-190. doi: 10.1016/j.imbio.2017.10.027.
13. Bavia L, Cogliati B, Dettoni JB, Ferreira Alves VA, Isaac L. (2016) The complement component C5 promotes liver steatosis and inflammation in murine non-alcoholic liver disease model. Immunology Letters;177:53-61. doi: 10.1016/j.imlet.2016.07.014.
14. Bavia L, de Castro ÍA, Cogliati B, Dettoni JB, Alves VA, Isaac L. (2016) Complement C5 controls liver lipid profile, promotes liver homeostasis and inflammation in C57BL/6 genetic background. Immunobiology;221(7):822-32.
15. da Silva KR, Fraga TR, Lucatelli JF, Grumach AS, Isaac L. (2016) Skipping of exon 27 in C3 gene compromises TED domain and results in complete human C3 deficiency. Immunobiology;221(5):641-9. doi: 10.1016/j.imbio.2016.01.005.
16. Fraga TR, Isaac L, Barbosa AS (2016) Complement Evasion by Pathogenic Leptospira. Frontiers in Immunology;7: 623. doi: 10.3389/fimmu.2016.00623.
17. Castiblanco-Valencia MM, Fraga TR, Breda LC, Vasconcellos SA, Figueira CP, Picardeau M, Wunder E, Ko AI, Barbosa AS, Isaac L (2016) Acquisition of negative complement regulators by the saprophyte Leptospira biflexa expressing LigA or LigB confers enhanced survival in human serum. Immunology Letters;173:61-68.
18. Castiblanco-Valencia MM, Fraga TR, Pagotto AH, de Toledo Serrano SM, Abreu PA, Barbosa AS, Isaac L (2016) 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;221:679-89.
19. Macedo AC, Isaac L. (2016) Systemic Lupus Erythematosus and Deficiencies of Early Components of the Complement Classical Pathway. Frontiers in Immunology;7:55. doi: 10.3389/fimmu.2016.00055.
20. Pekkarinen PT, Heikkilä N, Kisand K, Peterson P, Botto M, Daha MR, Drouet C, Isaac L, Helminen M, Haahtela T, Meri S, Jarva H, Arstila TP. (2015) Dysregulation of adaptive immune responses in complement C3-deficient patients. European Journal of Immunology;45(3):915-21. doi: 10.1002/eji.201444948.
21. avia L, de Castro ÍA, Isaac L. (2015) C57BL/6 and A/J Mice Have Different Inflammatory Response and Liver Lipid Profile in Experimental Alcoholic Liver Disease. Mediators in Inflammation;2015:491641. doi: 10.1155/2015/491641.
22. Breda LCD, Hsieh C, Castiblanco-Valencia, MM, Silva LB, Barbosa AS, Blom AM, Yung-Fu C, Isaac L (2015) Fine mapping of the interaction between C4b-binding protein and outer membrane proteins LigA and LigB of pathogenic Leptospira interrogans. PLoS Neglected Tropical Diseases;9: e0004286.
23. Silva LB, Miragaia LS, Breda LCD, Abe CM, Schmidt MCB, Moro AM, Monaris D, Conde JN, Józsi M, Isaac L, Abreu PAE, Barbosa AS (2015) Pathogenic Leptospira Species Acquire Factor H and Vitronectin via the Surface Protein LcpA. Infection and Immunity;83: 888-897.
24. Sahagún-Ruiz A, Breda LCD, Castiblanco, MM, Elias WP, Munthe-Fog L, Garred P, Barbosa AS, Isaac L (2015) 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;220: 1177-1185.
25. Abreu AG, Fraga TR, Martinez APG, Kondo MY, Juliano MA, Juliano L, Navarro-Garcia F, Isaac L, Barbosa AS, Elias WP (2015) The serine protease Pic from enteroaggregative Escherichia coli mediates immune evasion by the direct cleavage of complement proteins. The Journal of Infectious Diseases;212: 106-115.
26. Bavia L, de Castro ÍA, Massironi SM, Isaac L. (2014) Basal physiological parameters of two congenic mice strains: C5 deficient C57BL/6 and C5 sufficient A/J. Immunology Letters;159(1-2):47-54. doi: 10.1016/j.imlet.2014.02.010.
27. Fraga TR, Courrol D, Valencia MMC, Hirata IY, Vasconcellos SA, Juliano L, Barbosa AS, Isaac L (2014) Immune evasion by pathogenic Leptospira strains: the secretion of proteases that directly cleave complement proteins. The Journal of Infectious Diseases 209: 876-886.
28. Sahagún-Ruiz A, Granados-Martinez AP, Breda LCD, Fraga TR, Castiblanco-Valencia MM, Barbosa AS, Isaac L (2014) Pasteurella pneumotropica Evades the Human Complement System by Acquisition of the Complement Regulators Factor H and C4BP. Plos One 9: e111194.
29. Wolff DG, Castiblanco MM, Abe CM, Monaris D, Morais ZM, Souza GO, Vasconcellos AS, Isaac L, Abreu PAE, Barbosa AS (2013) Interaction of Leptospira Elongation Factor Tu with Plasminogen and Complement Factor H: A Metabolic Leptospiral Protein with Moonlighting Activities. Plos One 8: e81818.
30. Silva AS, Teixeira AG, Bavia L, Lin F, Velletri R, Belfort R Jr, Isaac L. (2012) Plasma levels of complement proteins from the alternative pathway in patients with age-related macular degeneration are independent of Complement Factor H Tyr⁴⁰²His polymorphism. Molecular Vision 18:2288-99.
31. Castiblanco-Valencia MM, Fraga TR, Silva LB, Monaris D, Abreu PAE, Strobel S,  Jozsi M, Isaac L, Barbosa AS (2012) Leptospiral Immunoglobulin-like Proteins Interact With Human Complement Regulators Factor H, FHL-1, FHR-1, and C4BP. Journal of Infectious Diseases; 205: 995-1004.
32. Albuquerque JA, Lamers ML, Castiblanco-Valencia MM, Dos Santos M, Isaac L. (2012) Chemical chaperones curcumin and 4-phenylbutyric acid improve secretion of mutant factor H R127H by fibroblasts from a factor H-deficient patient. Journal of Immunology;189(6):3242-8. doi: 10.4049/jimmunol.1201418.
33. Silva AS, Valencia MM, Cianciarullo AM, Vasconcellos SA, Barbosa AS, Isaac L. (2011) Interaction of human complement factor H variants Tyr⁴⁰² and His⁴⁰² with Leptospira spp. Frontiers in Immunology;2:44. doi: 10.3389/fimmu.2011.00044.
34. Fraga TR, Barbosa AS, Isaac L (2011) Leptospirosis: Aspects of Innate Immunity, Immunopathogenesis and Immune Evasion from the Complement System. Scandinavian Journal of Immunology;73: 408-419.

Capítulos de livros/Book chapters (2011-2021)

1. Fraga TR, Carvalho E, Isaac L, Barbosa AS. Leptospira and Leptospirosis. In: Yi-Wei Tang, Max Sussman, Dongyou Liu, Ian Poxton, Joseph Schwartzman. (Org.). Molecular Medical Microbiology. 2ªed. Amsterdam: Elsevier, 2014, v. III, p. 1973-1990.
2. Fraga TR, Carvalho E, Isaac L, Barbosa AS. Leptospira and Leptospirosis. In: Yi-Wei Tang, Max Sussman, Dongyou Liu, Ian Poxton, Joseph Schwartzman. (Org.). Molecular Medical Microbiology. 2ªed. Amsterdam: Elsevier, 2022, v. III in press.
3. Isaac L, Barbosa AS. Complement Resistance Assays. In: Methods Molecular Biology 2020;2134:187-198. doi:10.1007/978-1-0716-0459-5_17, 2020