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Master's Dissertation
DOI
https://doi.org/10.11606/D.17.2022.tde-06022023-111756
Document
Author
Full name
Bruna Manuella Souza Silva
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2022
Supervisor
Committee
Cunha, Thiago Mattar (President)
Bozza, Marcelo Torres
Fabro, Alexandre Todorovic
Title in Portuguese
O papel da sinalização do eixo C5a/C5aR1 na fisiopatologia COVID-19
Keywords in Portuguese
Complemento
NETs e COVID-19
Neutrófilo
Abstract in Portuguese
Os doentes com COVID-19 grave desenvolvem a síndrome do desconforto respiratório agudo (SDRA) que pode progredir para a tempestade de citocinas, disfunção de órgãos, consequentemente morte. Considerando que o fator do sistema complemento 5a (C5a), através do seu receptor celular C5aR1, apresenta potentes ações pró-inflamatórias, e desempenha papéis imunes e patológicos nas doenças inflamatórias, foi investigado se a via C5a/C5aR1 poderia estar envolvida na fisiopatologia da COVID-19. A sinalização de C5a/C5aR1 aumentou localmente no pulmão, especialmente nos neutrófilos de doentes graves com COVID-19 em comparação aos pacientes com pneumonia por influenza, suportando esse dado prévio o pulmão de camundongos K18-hACE2 (camundongos Tg, suscetíveis a infecção) infectados com SARS-COV-2 apresentaram aumento do C5a. A inibição genética e farmacológica da sinalização C5aR1 melhorou a imunopatologia pulmonar em camundongos infectados. Mecanisticamente, se descobriu que a sinalização do C5aR1 no contexto da infecção conduz a liberação de armadilha extracelular neutrofílica (NETs). Estes dados confirmam o papel fisiopatológico do eixo C5a/C5aR1 na amplificação da inflamação na COVID-19 e propõe como alternativa terapêutica antagonizar C5aR1.
Title in English
Role of axis C5a/C5aR1 in pathophysiology of COVID-19
Keywords in English
Complement
NETs and COVID-19
Neutrophil
Abstract in English
Patients with severe COVID-19 develop acute respiratory distress syndrome (ARDS) that can progress to cytokine storm, organ dysfunction, consequently death. Considering that complement system factor 5a (C5a), through its cellular receptor C5aR1, exhibits potent pro-inflammatory actions, and plays immune and pathological roles in inflammatory diseases, we investigated whether the C5a/C5aR1 pathway might be involved in the pathophysiology of COVID-19. C5a/C5aR1 signaling increased locally in the lung, especially in neutrophils of severely ill patients with COVID-19 compared to patients with influenza pneumonia, supporting this previous data the lung of K18-hACE2 mice (Tg mice, susceptible to infection) infected with SARS-COV-2 showed increased C5a. Genetic and pharmacological inhibition of C5aR1 signaling improved lung immunopathology in infected mice. Mechanistically, C5aR1 signaling in the context of infection was found to drive the release of extracellular neutrophil trapping (NETs). These data confirm the pathophysiological role of the C5a/C5aR1 axis in amplifying inflammation in COVID-19 and propose as a therapeutic alternative to antagonize C5aR1.
 
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Publishing Date
2023-02-08
 
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