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

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.

Mecanismos de biogênese e função dos corpúsculos lipídicos durante a infecção pelo vírus dengue

A dengue é caracterizada como a principal arbovirose humana, representando um grave problema de saúdepública. A superativação de células do sistema imune pode ser destacada como um dos fatores envolvidosna progressão da doença para as formas mais graves. Embora os monócitos sejam reconhecidos comoimportante fonte de citocinas, a participação das plaquetas na patogênese da dengue permanece poucoexplorada. Recentemente, nosso grupo mostrou a contribuição da interação plaqueta-monócito na respostainflamatória observada durante a dengue. De fato, o papel das plaquetas na resposta imune e inflamatória écada vez mais frequente. Dentro deste contexto, foi proposto que plaquetas ativadas por estímulo específicosinalizam para mudanças fenotípicas nos monócitos, incluindo a diferenciação em células espumosas que écaracterizada pelo aumento da biogênese de corpúsculos lipídicos (CL) – organelas citoplasmáticasdinâmicas ricas em lipídios relacionadas a processos inflamatórios e infecciosos. Nossos estudos préviosdemonstraram um aumento da biogênese de CL tanto em leucócitos isolados de pacientes com a formagrave da doença quanto em células infectadas com o vírus dengue (DENV) in vitro, com participação nalocalização da proteína do capsídeo viral e na produção de partículas virais infecciosas. Entretanto, osmecanismos que regulam a biogênese e a função destas organelas durante a infecção pelo DENV precisamser melhor caracterizados....

Dengue is characterized as the most important arthropod-borne human viral disease worldwide,representing a public health problem. Increased activation of immune cells could be involved in theprogression of disease to severe forms. Although monocytes have been recognized as important sources ofcytokines, the role of platelets in dengue pathogenesis remains understood. Recently our group showed thecontribution of platelet-monocyte interaction to inflammatory responses observed in dengue. In fact, it isbecoming increasingly clear that platelets have inflammatory functions and can influence innate response.Evidences suggest that specific stimuli-activated platelets can promote phenotypic changes in monocytes,including enhanced foam cell formation, that is characterized by an increase in lipid droplets (LD) –dynamic cytoplasmic lipid-rich organelles, associated to inflammatory and infectious conditions –biogenesis. Our previous works showed a significant increase in LD accumulation in leukocytes fromdengue hemorrhagic fever patients, as well as in different cell types infected in vitro. Besides, theseorganelles were involved in capsid protein localization and virus particle morphogenesis. However, themechanisms involved in LD biogenesis and function during dengue virus (DENV) infection still unclear...