Caspase-1/11 controls Zika virus replication in astrocytes by inhibiting glycolytic metabolism

Autor(es)

de Farias, Ingrid S. ; Ribeiro, Guilherme ; Noronha, Isau H. ; Lucena, Victoria Weise L. ; Peron, Jean P. S. ; Moraes-Vieira, Pedro M. ; Alves-Filho, Jose C. ; Bortoluci, Karina R.

• Tipo de documento: Artigo Científico
• Fonte: FEBS Journal; v. N/A, p. 16-pg., 2025-03-12.

Resumo

Zika virus (ZIKV) poses a significant threat due to its association with severe neurological complications, particularly during pregnancy. Although viruses exhibit tropism for neural cells, including astrocytes, the role of these cells in controlling ZIKV replication remains unclear. In this study, we demonstrated that ZIKV induces caspase-1 activation in primary astrocytes despite the absence of classical signs of inflammasome activation. Caspase-1 and caspase-11 double knockout (caspase-1/11-/-) astrocytes exhibit heightened permissiveness to viral replication, accompanied by overactivation of glycolytic metabolism. Inhibition of glycolysis reversed the susceptibility of caspase-1/11-/- astrocytes to ZIKV infection. Protein network analysis revealed mammalian target of rapamycin complex (mTORC) as a link between proteins involved in glycolysis and caspase-1, and mTORC inhibition also suppressed viral replication. Furthermore, we found that the impact of caspase-1/11 on astrocytes depends on the regulation of pyruvate transport to mitochondria for viral replication. Overall, our findings elucidate a caspase-1/11-dependent microbicidal mechanism in astrocytes that involves the mTORC/glycolytic pathway/pyruvate axis, providing insights into potential therapeutic targets for ZIKV infection. (AU)

• Processo FAPESP: 20/13493-9 - Avaliação da ativação diferencial dos inflamassomas em células gliais e neurônios murinos e humanos em resposta ao SARS-CoV-2
• Beneficiário: Ingrid Sancho de Farias
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 18/19411-4 - Papel dos inflamassomas no controle da infecção por ZIKV em células gliais
• Beneficiário: Ingrid Sancho de Farias
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 21/03371-6 - Impacto da ativação dos inflamassomas no sistema nervoso central em resposta a ZikV e SARS-Cov2
• Beneficiário: Karina Ramalho Bortoluci
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 23/16013-6 - Papel das Moléculas Efetoras da Piroptose e Lise Celular na Regulação Metabólica e Controle da Infecção por Toxoplasma gondii
• Beneficiário: Karina Ramalho Bortoluci
• Modalidade de apoio: Auxílio à Pesquisa - Regular