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The role of HIF1a in dendritic cells to control inflammation during the acute and chronic phase in the Chikungunya

Grant number: 22/00905-2
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): May 01, 2022
Effective date (End): April 30, 2023
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal researcher:José Luiz Proença Módena
Grantee:Gabriela Fabiano de Souza
Supervisor abroad: Deborah Jane Lenschow
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Research place: University of Washington, United States  
Associated to the scholarship:18/10224-7 - The role of activation and metabolic imbalance of dendritic cells for Chikungunya virus pathogenesis, BP.DR

Abstract

The Chikungunya virus (CHIKV) is an emerging arbovirus present in tropical and subtropical regions. One of the major complications associated with CHIKV infection are chronic manifestations such as arthralgia and arthritis. The chronic disease resulting from CHIKV infection has similar characteristics to rheumatoid arthritis (RA) in which dendritic cells (DCs) are implicated in the pathogenesis. Thus, we believe that the metabolic imbalance of DCs may play an essential role in the pathogenesis of CHIKV and in the development of chronic inflammation. To analyze the effect of CHIKV on the function and metabolism of DCs, we isolated and differentiate DCs from wild-type murine bone-marrow cells (BMDCs). We treated cells with key metabolic sensors 2-DG (glycolysis inhibitor), BAY 85 and 87 (HIF stabilization and inhibitor) before infection. None of the inhibitors reduced the viral load but affected genes and cytokines important for the antiviral response. In BMDCs, when HIF was stabilized or inhibited, we had an increase in glycolytic enzymes involved in inflammation. Interestingly, during infection, HIF inhibition reduced IL1² and IL6, and increased IL10 expression. Our hypothesis is that HIF could be transcriptionally regulating IL10 expression and establishing a glycolytic metabolism in DCs which could contribute to inflammation during chronic disease. Finally, we analyzed the role of HIF-1± in dendritic cells during CHIKV infection. We observed that in CD11ccreHIF-1±fl/fl mice there was a dramatic increase in footpad swelling during acute infection. In addition, we observed a 500-fold higher level of viral RNA in the footpads of CD11ccreHIF1± mice as compared to WT mice 21 days post-infection. These results implicate HIF-1± in the regulation of inflammation and metabolism in dendritic cells, during CHIKV pathogenesis.

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