The largest ever recorded epidemic of the Chikungunya virus (CHIKV) broke out in 2004 and affected four continents. Acute symptomatic infections are typically associated with the onset of fever and often debilitating polyarthralgia/polyarthritis. In this study, a systems biology approach was adopted to analyze the blood transcriptomes of adults acutely infected with the CHIKV. Gene signatures that were associated with viral RNA levels and the onset of symptoms were identified. Among these genes, the putative role of the Eukaryotic Initiation Factor (eIF) family genes and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC3A) in the CHIKV replication process were displayed. We further compared these signatures with signatures induced by the Dengue virus infection and rheumatoid arthritis. Finally, we demonstrated that the CHIKV in vitro infection of murine bone marrow-derived macrophages induced IL-1 beta production in a mechanism that is significantly dependent on the inflammasome NLRP3 activation. The observations provided valuable insights into virus-host interactions during the acute phase and can be instrumental in the investigation of new and effective therapeutic interventions.

Análise transcritômica de amostras humanas naturalmente infectadas por Virus Chikungunya São Paulo AgradecimentosAgradeço aos meus pais por todo o suporte e ajuda oferecido em todos os momentos de minha vida, imprescindível para que tudo isso fosse possível.Agradeço ao Matheus Calil por toda paciência e amor que me oferece em todos os momentos. toda a ajuda durante esses 2 anos, seja na questão técnica quanto com uma conversa cercada de café. Vocês com certeza tornaram esta jornada mais leve e com muito aprendizado.Agradeço a Alessandra Schanoski pela oportunidade de um trabalho em conjunto. Agradeço a Prof. Helder Nakaya que acreditou no meu potencial e permitiu que eu me desenvolvesse em seu laboratório. Agradeço a Fundação Bill e Melinda Gates pelo apoio financeiro que garantiu que este projeto fosse realizado. À Universidade de Sâo Paulo, pela oportunidade de realizar esta pós-graduação. Aos pacientes utilizados neste trabalho pois sem o auxílio deles esta pesquisa não existiria. Abstract Baptista-Cruz, Natalia. Transcriptional analysis of human samples naturally infected by Chikungunya Virus. 2019. Dissertation (Master of Science) -University of São Paulo, São Paulo, 2019 The Chikungunya Fever is a systemic disease transmitted by arboviruses and is estimated to affect 1 million people annually. The main symptoms associated with this disease are fever and polyarthralgia, which can develop to chronic features in about half of the cases. Due to outbreaks that occurred in the last 50 years, many studies had the goal of determining the mechanisms of virus replication and immune response. Nevertheless, it is still poorly understood which molecules enable the ocurrence of the infection process. It has already been shown the importance of interferons, mainly type I, cytokines and chemokines in restricting the viral replication.In addition, the Chikungunya virus shows a preference for specific cell types such as endothelial and epithelial cells. However, studies display contradictory information regarding the role of peripheral blood mononuclear cells (PBMC), mainly in relation to monocytes and B and T cells. Given this context, the treatment currently used is directed only to alleviate the symptoms since there are no specific licensed drugs or vaccines for this disease. Therefore, the objective of this work was to study the transcriptional modifications that occur in humans during the process of Chikungunya virus infection in order to clarify the mechanisms used by the immune system. In addition, it aims to point out possible transcriptional differences between sample from the Chronic and Non-Chronic acute phase of the infection.