Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators
Autor: | Suelen da Silva Gomes Dias, Lívia Teixeira, Eugenio D. Hottz, Carolina Q. Sacramento, Caroline S. de Freitas, Mayara Mattos, Vinicius Cardoso Soares, Camila R. R. Pão, André C. Ferreira, Isaclaudia G. de Azevedo-Quintanilha, Thiago Moreno L. Souza, Marcos Alexandre Nunes da Silva, Milene D. Miranda, Patrícia T. Bozza, Marilda M. Siqueira, Natalia Fintelman-Rodrigues, Ester A. Barreto, Jairo R. Temerozo, Fernando A. Bozza, Debora Ferreira Barreto-Vieira, Dumith Chequer Bou-Habib, Pedro P.A. Manso |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
RNA viruses
Viral Diseases Pulmonology Coronaviruses CD36 viruses Virus Replication Biochemistry Monocytes White Blood Cells 0302 clinical medicine Medical Conditions Animal Cells Lipid droplet Chlorocebus aethiops Biology (General) Immune Response Pathology and laboratory medicine 0303 health sciences Medical microbiology Lipids Cell biology Infectious Diseases Viruses medicine.symptom Inflammation Mediators SARS CoV 2 Pathogens Cellular Types Research Article SARS coronavirus QH301-705.5 Immune Cells Immunology Inflammation Biology Biosynthesis Microbiology 03 medical and health sciences Respiratory Disorders Signs and Symptoms Virology Organelle Genetics medicine Animals Humans Molecular Biology Vero Cells 030304 developmental biology Medicine and health sciences Blood Cells Biology and life sciences SARS-CoV-2 Intracellular parasite Organisms Viral pathogens COVID-19 Lipid metabolism Covid 19 Lipid Droplets Cell Biology RC581-607 Lipid Metabolism Viral Replication Microbial pathogens Metabolism Viral replication Case-Control Studies Respiratory Infections Vero cell biology.protein Parasitology Clinical Medicine Immunologic diseases. Allergy 030217 neurology & neurosurgery |
Zdroj: | PLoS Pathogens, Vol 16, Iss 12, p e1009127 (2020) PLoS Pathogens |
ISSN: | 1553-7374 1553-7366 |
Popis: | 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. Author summary In spite of the enormous scientific efforts to understand mechanisms of SARS-CoV2-induced disease and to develop strategies to control COVID-19 pandemic, many aspects of SARS-CoV2 biology and pathogenesis remain elusive. Several RNA viruses are able to modulate the host lipid metabolism and to recruit LDs to enhance their replication/particle assembling capacity through mechanisms that vary according to the virus and the host cell infected. The mechanisms and pathways explored by SARS-CoV-2 to support its replication within host cells are still largely unknown. Here we demonstrated that lipid droplets (LDs) participate in SARS-CoV2 infection favoring virus replication and heightening inflammatory mediator production. SARS-CoV2 infection increased the expression of key proteins in the regulation of lipid metabolism and the amounts of LDs per cell. In addition, we have found SARS-CoV2 and/or its components associated with LDs in infected cells, suggestive that LDs are recruited as part of replication compartment. Moreover, pharmacological inhibition of DGAT-1, a key enzyme for LD formation, reduces SARS-CoV2 replication, inflammatory mediator production and cell death. Our findings contribute to unveil the complex mechanism by which SARS-CoV-2 make use of cellular metabolism and organelles to coordinate different steps of the viral replication cycle and host immunity, opening new perspectives for SARS-CoV2 antiviral development. |
Databáze: | OpenAIRE |
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