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ALLELE-DEPENDENT INTERACTION OF LRRK2 AND NOD2 IN LEPROSY
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Nod2 Signaling Adaptor Protein
Mycobacterium bovis
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina
Proteína Adaptadora de Señalización NOD2
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina
Proteína Adaptadora de Sinalização NOD2
Bacillus Calmette-Guérin
Autor
Dallmann-Sauer, Monica
Xu, Yong Zhong
Costa, Ana Lúcia França da
Tao, Shao
Gomes, Tiago Araujo
Prata, Rhana Berto da Silva
Correa- Macedo, Wilian
Manry, Jérémy
Alcaïs, Alexandre
Abel, Laurent
Cobat, Aurélie
Fava, Vinicius M.
Pinheiro, Roberta Olmo
Lara, Flavio Alves
Probst, Christian Macagnan
Mira, Marcelo T.
Schurr, Erwin
Xu, Yong Zhong
Costa, Ana Lúcia França da
Tao, Shao
Gomes, Tiago Araujo
Prata, Rhana Berto da Silva
Correa- Macedo, Wilian
Manry, Jérémy
Alcaïs, Alexandre
Abel, Laurent
Cobat, Aurélie
Fava, Vinicius M.
Pinheiro, Roberta Olmo
Lara, Flavio Alves
Probst, Christian Macagnan
Mira, Marcelo T.
Schurr, Erwin
Afiliación
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada. / Departments of Human Genetics and Medicine. Faculty of Medicine and Health Science. McGill University. Montreal, Canada. / Pontifícia Universidade Católica do Paraná. Escola de Medicina e Ciências da Vida. Programa de Pós-Graduação em Ciências da Saúde. Curitiba, PR, Brasil.
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada.
Universidade Federal do Piauí. Centro de Ciências da Saúde. Departamento de Medicina Especializada. Teresina, PI, Brasil.
Division of Experimental Medicine. Faculty of Medicine. McGill University. Montreal, Canada. / The Translational Research in Respiratory Diseases Program. The Research Institute of the McGill University Health Centre. Montreal, Canada.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Leprosia. Rio de Janeiro, RJ, Brasil.
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada. / Department of Biochemistry. Faculty of Medicine and Health Science. McGill University. Montreal, Canada.
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada.
Laboratory of Human Genetics of Infectious Diseases. Necker Branch. Institut National de la Santé et de la Recherche Médicale. Paris, France. / Université Paris Cité. Imagine Institute. Paris, France.
Laboratory of Human Genetics of Infectious Diseases. Necker Branch. Institut National de la Santé et de la Recherche Médicale. Paris, France. / Université Paris Cité. Imagine Institute. Paris, France. / St. Giles Laboratory of Human Genetics of Infectious Diseases. Rockefeller Branch. Rockefeller University. New York, United States of America.
Laboratory of Human Genetics of Infectious Diseases. Necker Branch. Institut National de la Santé et de la Recherche Médicale. Paris, France. / Université Paris Cité. Imagine Institute. Paris, France. / St. Giles Laboratory of Human Genetics of Infectious Diseases. Rockefeller Branch. Rockefeller University. New York, United States of America.
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Leprosia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Biologia Molecular e Sistêmica de Tripanossomatídeos. Curitiba, PR, Brasil.
Pontifícia Universidade Católica do Paraná. Escola de Medicina e Ciências da Vida. Programa de Pós-Graduação em Ciências da Saúde. Curitiba, PR, Brasil.
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada. / Department of Biochemistry. Faculty of Medicine and Health Science. McGill University. Montreal, Canada.
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada.
Universidade Federal do Piauí. Centro de Ciências da Saúde. Departamento de Medicina Especializada. Teresina, PI, Brasil.
Division of Experimental Medicine. Faculty of Medicine. McGill University. Montreal, Canada. / The Translational Research in Respiratory Diseases Program. The Research Institute of the McGill University Health Centre. Montreal, Canada.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Leprosia. Rio de Janeiro, RJ, Brasil.
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada. / Department of Biochemistry. Faculty of Medicine and Health Science. McGill University. Montreal, Canada.
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada.
Laboratory of Human Genetics of Infectious Diseases. Necker Branch. Institut National de la Santé et de la Recherche Médicale. Paris, France. / Université Paris Cité. Imagine Institute. Paris, France.
Laboratory of Human Genetics of Infectious Diseases. Necker Branch. Institut National de la Santé et de la Recherche Médicale. Paris, France. / Université Paris Cité. Imagine Institute. Paris, France. / St. Giles Laboratory of Human Genetics of Infectious Diseases. Rockefeller Branch. Rockefeller University. New York, United States of America.
Laboratory of Human Genetics of Infectious Diseases. Necker Branch. Institut National de la Santé et de la Recherche Médicale. Paris, France. / Université Paris Cité. Imagine Institute. Paris, France. / St. Giles Laboratory of Human Genetics of Infectious Diseases. Rockefeller Branch. Rockefeller University. New York, United States of America.
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Leprosia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Biologia Molecular e Sistêmica de Tripanossomatídeos. Curitiba, PR, Brasil.
Pontifícia Universidade Católica do Paraná. Escola de Medicina e Ciências da Vida. Programa de Pós-Graduação em Ciências da Saúde. Curitiba, PR, Brasil.
Program in Infectious Diseases and Immunity in Global Health. The Research Institute of the McGill University Health Centre. Montreal, Canada. / McGill International TB Centre. McGill University. Montreal, Canada. / Department of Biochemistry. Faculty of Medicine and Health Science. McGill University. Montreal, Canada.
Resumen en ingles
Leprosy, caused by Mycobacterium leprae, rarely affects children younger than 5 years. Here, we studied a multiplex leprosy family that included monozygotic twins aged 22 months suffering from paucibacillary leprosy. Whole genome sequencing identified three amino acid mutations previously associated with Crohn’s disease and Parkinson’s disease as candidate variants for early onset leprosy: LRRK2 N551K, R1398H and NOD2 R702W. In genome-edited macrophages, we demonstrated that cells expressing the LRRK2 mutations displayed reduced apoptosis activity following mycobacterial challenge independently of NOD2. However, employing co-immunoprecipitation and confocal microscopy we showed that LRRK2 and NOD2 proteins interacted in RAW cells and monocyte-derived macrophages, and that this interaction was substantially reduced for the NOD2 R702W mutation. Moreover, we observed a joint effect of LRRK2 and NOD2 variants on Bacillus Calmette-Guérin (BCG)-induced respiratory burst, NF-κB activation and cytokine/chemokine secretion with a strong impact for the genotypes found in the twins consistent with a role of the identified mutations in the development of early onset leprosy.
Palabras clave en portugues
Proteína LRRK2Palabras clave en ingles
Leprosy, PaucibacillaryLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
Nod2 Signaling Adaptor Protein
Mycobacterium bovis
Palabras clave
Lepra PaucibacilarProteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina
Proteína Adaptadora de Señalización NOD2
DeCS
Hanseníase PaucibacilarSerina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina
Proteína Adaptadora de Sinalização NOD2
Bacillus Calmette-Guérin
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