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https://www.arca.fiocruz.br/handle/icict/25404
A FASHILYMPHOPROLIFERATIVE PHENOTYPE REVEALS NON-APOPTOTIC FAS SIGNALING IN HTLV-1-ASSOCIATED NEUROINFLAMMATION
Proliferação
Mielopatia associada ao HTLV-1 / paraparesia espástica tropical
Doença linfoproliferativa
Apoptose
Interferão
NF-κB
Esclerose múltipla
Proliferation
HTLV-1-associated myelopathy/tropical spastic paraparesis,
Lymphoproliferative disease
Apoptosis
Interferon
NF-κB
Multiple sclerosis
Author
Menezes, Soraya Maria
Leal, Fabio Eudes
Dierckx, Tim
Cunha, Antonio Ricardo Khouri
Decanine, Daniele
Santos, Gilvaneia Silva
Schnitman, Saul V
Kruschewsky, Ramon
López, Giovanni
Alvarez, Carolina
Talledo, Michael
Gotuzzo, Eduardo
Nixon, Douglas F
Vercauteren, Jurgen
Brassat, David
Liblau, Roland
Vandamme, Anne Mieke
Castro Filho, Bernardo Galvão
Van Weyenbergh, Johan Josef Roza Maria
Leal, Fabio Eudes
Dierckx, Tim
Cunha, Antonio Ricardo Khouri
Decanine, Daniele
Santos, Gilvaneia Silva
Schnitman, Saul V
Kruschewsky, Ramon
López, Giovanni
Alvarez, Carolina
Talledo, Michael
Gotuzzo, Eduardo
Nixon, Douglas F
Vercauteren, Jurgen
Brassat, David
Liblau, Roland
Vandamme, Anne Mieke
Castro Filho, Bernardo Galvão
Van Weyenbergh, Johan Josef Roza Maria
Affilliation
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium
The George Washington University. Immunology & Tropical Medicine Department of Microbiology. Washington, DC, USA
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil
Bahiana School of Medicine and Public Health. Salvador, BA, Brazil
Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium / Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru
Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru
Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru / Hospital Cayetano Heredia. Departamento de Enfermedades Infecciosas,Tropicales y Dermatológicas. Lima, Peru
The George Washington University. Immunology & Tropical Medicine Department of Microbiology. Washington, DC, USA
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium
Université de Toulouse. Hôpital Purpan. Inserm and Pôle des Neurosciences. Toulouse, France
Université de Toulouse. Hôpital Purpan. Inserm and Pôle des Neurosciences. Toulouse, France
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium / Universidade Nova de Lisboa. Instituto de Higiene e Medicina Tropical. Center for Global Health and Tropical Medicine. Unidade de Microbiologia. Lisbon, Portugal
Bahiana School of Medicine and Public Health. Salvador, BA, Brazil
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium
The George Washington University. Immunology & Tropical Medicine Department of Microbiology. Washington, DC, USA
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium / Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil
Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Laboratório de Enfermidades Infecciosas Transmitidas por Vetores. Salvador, BA, Brasil
Bahiana School of Medicine and Public Health. Salvador, BA, Brazil
Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium / Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru
Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru
Universidad Peruana Cayetano Heredia. Instituto de Medicina Tropical Alexander von Humboldt. Lima, Peru / Hospital Cayetano Heredia. Departamento de Enfermedades Infecciosas,Tropicales y Dermatológicas. Lima, Peru
The George Washington University. Immunology & Tropical Medicine Department of Microbiology. Washington, DC, USA
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium
Université de Toulouse. Hôpital Purpan. Inserm and Pôle des Neurosciences. Toulouse, France
Université de Toulouse. Hôpital Purpan. Inserm and Pôle des Neurosciences. Toulouse, France
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium / Universidade Nova de Lisboa. Instituto de Higiene e Medicina Tropical. Center for Global Health and Tropical Medicine. Unidade de Microbiologia. Lisbon, Portugal
Bahiana School of Medicine and Public Health. Salvador, BA, Brazil
Rega Institute for Medical Research. Clinical and Epidemiological Virology. Department of Microbiology and Immunology. KU Leuven, Leuven, Belgium
Abstract
Human T-cell lymphotropic virus (HTLV)-1 was the first human retrovirus to be associated to cancer, namely adult T-cell leukemia (ATL), but its pathogenesis remains enigmatic, since only a minority of infected individuals develops either ATL or the neuroinflammatory disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A functionalFAS-670 polymorphism in an interferon (IFN)-regulated STAT1-binding site has been associated to both ATL and HAM/TSP susceptibility. FashiT stem cell memory (Tscm) cells have been identified as the hierarchical apex of ATL, but have not been investigated in HAM/TSP. In addition, bothFASandSTAT1have been identified in an IFN-inducible HAM/TSP gene signature, but its pathobiological significance remains unclear. We comprehensively explored Fas expression (protein/mRNA) and function in lymphocyte activation, apoptosis, proliferation, and transcriptome, in PBMC from a total of 47 HAM/TSP patients, 40 asymptomatic HTLV-1-infected individuals (AC), and 58 HTLV-1 -uninfected healthy controls. Fas surface expression followed a two-step increase from HC to AC and from AC to HAM/TSP. In HAM/TSP, Fas levels correlated positively to lymphocyte activation markers, but negatively to age of onset, linking Fashicells to earlier, more aggressive disease. Surprisingly, increased lymphocyte Fas expression in HAM/TSP was linked to decreased apoptosis and increased lymphoproliferation uponin vitroculture, but not to proviral load. This Fashiphenotype is HAM/TSP-specific, since bothex vivoandin vitroFas expression was increased as compared to multiple sclerosis (MS), another neuroinflammatory disorder. To elucidate the molecular mechanism underlying non-apoptotic Fas signaling in HAM/TSP, we combined transcriptome analysis with functional assays, i.e., blocking vs. triggering Fas receptorin vitrowith antagonist and agonist-, anti-Fas mAb, respectively. Treatment with agonist anti-Fas mAb restored apoptosis, indicating biased, but not defective Fas signaling in HAM/TSP.In silicoanalysis revealed biased Fas signaling toward proliferation and inflammation, driven by RelA/NF-κB. Correlation of Fas transcript levels with proliferation (but not apoptosis) was confirmed in HAM/TSPex vivotranscriptomes. In conclusion, we demonstrated a two-step increase in Fas expression, revealing a unique Fashilymphocyte phenotype in HAM/TSP, distinguishable from MS. Non-apoptotic Fas signaling might fuel HAM/TSP pathogenesis, through increased lymphoproliferation, inflammation, and early age of onset.
Keywords in Portuguese
Fas / CD95Proliferação
Mielopatia associada ao HTLV-1 / paraparesia espástica tropical
Doença linfoproliferativa
Apoptose
Interferão
NF-κB
Esclerose múltipla
Keywords
Fas/CD95Proliferation
HTLV-1-associated myelopathy/tropical spastic paraparesis,
Lymphoproliferative disease
Apoptosis
Interferon
NF-κB
Multiple sclerosis
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