Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators

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.

Cyclooxygenase (COX)-2 modulates Toxoplasma gondii infection, immune response and lipid droplets formation in human trophoblast cells and villous explants

“…LDs are involved in a variety of functions, such as lipid metabolism, cell signaling, and they are found in inflammatory and infectious conditions 23 – 25 . In recent years, several studies have shown that many pathogens target LDs, including viruses 26 – 30 , intracellular bacteria 31 – 34 and protozoan 35 – 38 . These pathogens are known to seek lipid resources for their maintenance and survival, however studies have showed that LDs also can be central mediators of immune responses 22 , 39 .…”

Metabolic Alterations in SARS-CoV-2 Infection and Its Implication in Kidney Dysfunction

“…The lipid bodies have been described as a source of inflammatory mediators and contribute to pathogen escape from immune system elimination (D' Avila et al, 2006(D' Avila et al, , 2008Mattos et al, 2011;Almeida et al, 2014). Dias et al (2020) observed the colocalization of lipid bodies and SARS-CoV-2, suggesting them as a fuel for viral replication. The inhibition of lipid bodies formation reduced the viral load, cell death, and levels of inflammatory mediators.…”

“…Diglycerides, free fatty acids, and triglycerides were identified in higher amounts in the fatality group (Wu et al, 2020). Furthermore, ex vivo and in vitro studies reported increased viral replication in cells with excessive intracellular lipid accumulation (Dias et al, 2020). These initial findings suggest that in SARS-CoV-2 infection, systemic and cell lipid metabolism disturbances can be critical event in COVID-19 progression.…”

“…However, cellular and molecular mechanisms that orchestrate lipid metabolism during SARS-CoV-2 infection are poorly described so far. Recently, it was observed the lipid bodies formation in monocytes from infected patients and in vitro assay of SARS-CoV-2 infection (Dias et al, 2020). The lipid bodies have been described as a source of inflammatory mediators and contribute to pathogen escape from immune system elimination (D' Avila et al, 2006(D' Avila et al, , 2008Mattos et al, 2011;Almeida et al, 2014).…”

“…An investigation with 33 diagnosed patients with COVID-19 in comparison with COVID-19-negative individuals demonstrated that altered metabolite levels of the fatty acid and tryptophan metabolism in infected patients were correlated with clinical markers of inflammation (IL-6 and C-reactive protein) and renal function (BUN and creatinine; Thomas et al, 2020). Besides, in vitro studies demonstrated the SARS-CoV-2 potential of modulating the lipid metabolism in monocytes and lung epithelial cells (Dias et al, 2020). The abnormal metabolism functioning is critical for renal injury development, which makes systemic and cellular metabolism in COVID-19 an exciting issue of investigation for further studies in the context of renal injury.…”