Suelen Silva Gomes Dias1, Vinicius Cardoso Soares1,2, André C Ferreira1,3,4, Carolina Q Sacramento1,3, Natalia Fintelman-Rodrigues1,3, Jairo R Temerozo5, Lívia Teixeira1, Marcos Alexandre Nunes da Silva6, Ester Barreto1, Mayara Mattos1,3, Caroline S de Freitas1,3, Isaclaudia G Azevedo-Quintanilha1, Pedro Paulo A Manso7, Milene D Miranda8, Marilda Mendonça Siqueira8, Eugenio D Hottz1,9, Camila R R Pão1, Dumith C Bou-Habib5, Debora F Barreto-Vieira6, Fernando A Bozza10,11, Thiago M L Souza1,3, Patricia T Bozza1. 1. Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Rio de Janeiro, Brazil. 2. Programa de Imunologia e Inflamação, Universidade Federal do Rio de Janeiro, UFRJ, Rio de Janeiro, Rio de Janeiro, Brazil. 3. Centro De Desenvolvimento Tecnológico Em Saúde (CDTS) and National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDNP), FIOCRUZ, Rio de Janeiro, Brasil. 4. Universidade Iguaçu, Nova Iguaçu, Rio de Janeiro, Brazil. 5. Laboratório de Pesquisas sobre o Timo and Instituto National de Ciencia e Tecnologia em Neuroimunomodulação (INCT/NIM), Instituto Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Rio de Janeiro, Brazil. 6. Laboratório de Morfologia e Morfogênese Viral, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Rio de Janeiro, Brazil. 7. Laboratorio de Patologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Rio de Janeiro, Brazil. 8. Laboratório de Vírus Respiratórios e do Sarampo, Instituto Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Rio de Janeiro, Brazil. 9. Laboratorio de Imunotrombose, Departamento de Bioquímica, Universidade Federal de Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil. 10. Instituto Nacional de Infectologia Evandro Chagas (INI), FIOCRUZ, Rio de Janeiro, Brazil. 11. Instituto D'Or de Pesquisa e Ensino (IDOR), Rio de Janeiro, Brazil.
Abstract
Viruses are obligate intracellular parasites that make use of the host metabolic machineries to meet their biosynthetic needs. Thus, identifying the host pathways essential for the virus replication may lead to potential targets for therapeutic intervention. The mechanisms and pathways explored by SARS-CoV-2 to support its replication within host cells are not fully known. Lipid droplets (LD) are organelles with major functions in lipid metabolism, energy homeostasis and intracellular transport, and have multiple roles in infections and inflammation. Here we described that monocytes from COVID-19 patients have an increased LD accumulation compared to SARS-CoV-2 negative donors. In vitro, SARS-CoV-2 infection were seen to modulate pathways of lipid synthesis and uptake as monitored by testing for CD36, SREBP-1, PPARγ, and DGAT-1 expression in monocytes and triggered LD formation in different human cell lines. LDs were found in close apposition with SARS-CoV-2 proteins and double-stranded (ds)-RNA in infected Vero cells. Electron microscopy (EM) analysis of SARS-CoV-2 infected Vero cells show viral particles colocalizing with LDs, suggestive that LDs might serve as an assembly platform. Pharmacological modulation of LD formation by inhibition of DGAT-1 with A922500 significantly inhibited SARS-CoV-2 replication as well as reduced production of mediators pro-inflammatory response. Taken together, we demonstrate the essential role of lipid metabolic reprograming and LD formation in SARS-CoV-2 replication and pathogenesis, opening new opportunities for therapeutic strategies to COVID-19.
Viruses are obligate intracellular parasites that make use of the host metabolic machineries to meet their biosynthetic needs. Thus, identifying the host pathways essential for the virus replication may lead to potential targets for therapeutic intervention. The mechanisms and pathways explored by SARS-CoV-2 to smical">pan class="Gene">upport its replication within host cells are not fully known. Lipid droplets (LD) are organelles with major functions in lipid metabolism, energy homeostasis and intracellular transport, and have multiple roles in infections and inflammation. Here we described that monocytes from COVID-19patients have an increased LD accumulation compared to SARS-CoV-2 negative donors. In vitro, SARS-CoV-2 infection were seen to modulate pathways of lipid synthesis and uptake as monitored by testing for CD36, SREBP-1, PPARγ, and DGAT-1 expression in monocytes and triggered LD formation in different human cell lines. LDs were found in close apposition with SARS-CoV-2 proteins and double-stranded (ds)-RNA in infected Vero cells. Electron microscopy (EM) analysis of SARS-CoV-2 infected Vero cells show viral particles colocalizing with LDs, suggestive that LDs might serve as an assembly platform. Pharmacological modulation of LD formation by inhibition of DGAT-1 with A922500 significantly inhibited SARS-CoV-2 replication as well as reduced production of mediators pro-inflammatory response. Taken together, we demonstrate the essential role of lipid metabolic reprograming and LD formation in SARS-CoV-2 replication and pathogenesis, opening new opportunities for therapeutic strategies to COVID-19.
Authors: Christian Setz; Maximilian Große; Janina Auth; Maria Fröba; Pia Rauch; Alexander Bausch; Matthew Wright; Ulrich Schubert Journal: Int J Mol Sci Date: 2022-06-20 Impact factor: 6.208
Authors: Temidayo S Omolaoye; Nour Jalaleddine; Walter D Cardona Maya; Stefan S du Plessis Journal: Front Physiol Date: 2022-05-23 Impact factor: 4.755