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
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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