Metabolic reprogramming and lipid droplets are involved in Zika virus replication in neural cells

Suelen Silva Gomes Dias, Tamires Cunha-Fernandes, Luciana Souza-Moreira, Vinicius Cardoso Soares, Giselle Barbosa Lima, Isaclaudia G. Azevedo-Quintanilha, Julia Santos, Filipe Pereira-Dutra, Caroline Freitas, Patricia A. Reis, Stevens Kastrup Rehen, Fernando A. Bozza, Thiago M. Lopes Souza, Cecilia J. G. de Almeida, Patricia T. Bozza

Zika virus (ZIKV) infection is a global public health concern linked to adult neurological disorders and congenital diseases in newborns. Host lipid metabolism, including lipid droplet (LD) biogenesis, has been associated with viral replication and pathogenesis of different viruses. However, the mechanisms of LD formation and their roles in ZIKV infection in neural cells are still unclear. Here, we demonstrate that ZIKV regulates the expression of pathways associated with lipid metabolism, including the upregulation and activation of lipogenesis-associated transcription factors and decreased expression of lipolysis-associated proteins, leading to significant LD accumulation in human neuroblastoma SH-SY5Y cells and in neural stem cells (NSCs). Pharmacological inhibition of DGAT-1 decreased LD accumulation and ZIKV replication in vitro in human cells and in an in vivo mouse model of infection. In accordance with the role of LDs in the regulation of inflammation and innate immunity, we show that blocking LD formation has major roles in inflammatory cytokine production in the brain. Moreover, we observed that inhibition of DGAT-1 inhibited the weight loss and mortality induced by ZIKV infection in vivo. Our results reveal that LD biogenesis triggered by ZIKV infection is a crucial step for ZIKV replication and pathogenesis in neural cells. Therefore, targeting lipid metabolism and LD biogenesis may represent potential strategies for anti-ZIKV treatment development.