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Review 2: "Lipid droplets fuels SARS-CoV-2 replication and inflammatory response"

This study claims infection-mediated lipid droplet biogenesis contributes to SARS-CoV-2 replication while suppressing lipid droplet formation restricts infection. However, these are not fully substantiated by the data offered due to lack of proper controls.

Published onSep 21, 2020
Review 2: "Lipid droplets fuels SARS-CoV-2 replication and inflammatory response"
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key-enterThis Pub is a Review of
Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators
Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators

Viruses are obligate intracellular parasites that make use of the host metabolic machineries to meet their biosynthetic needs, 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 and energy homeostasis, and have multiple roles in infections and inflammation. Here we demonstrate that monocytes from COVID-19 patients have an increased LD accumulation compared to SARS-CoV-2 negative donors. In vitro, SARS-CoV-2 infection modulates pathways of lipid synthesis and uptake, as CD36, SREBP-1, PPARγ and DGAT-1 in human monocytes and triggered LD formation in different human cells. LDs were found in close apposition with SARS-CoV-2 proteins and double-stranded (ds)-RNA. The pharmacological modulation of LD formation by inhibition of DGAT-1 with A922500 significantly inhibited SARS-CoV-2 replication as well as reduced production of pro-inflammatory mediators. 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.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



The manuscript by da Silva Gomes Dias et al. describes the induction of lipid droplets in human monocytes taken from SARS-CoV-2 infected patients, as well as in cultured cell lines. It also demonstrates that inhibition of viral driven lipid droplet formation inhibits viral replication, as well as decreases cell death and the production of pro-inflammatory cytokines. This work offers further insight into the complex role of the lipid droplet in the context of viral infection, however, draws some definitive conclusions without sufficient evidence.

The induction of lipid droplets is a well shown phenomenon following many infectious diseases including bacteria and parasites, and there is evidence also demonstrating that activation of pattern recognition receptors can drive this response, suggesting it is a host driven response initially, rather than a pathogen driven response. However, the exact purpose of this event remains largely unknown. Additionally, it is well documented that multiple viruses alter the lipid dynamics in their host cells to further their replication cycle, and it appears from the data presented in this manuscript, that it is likely that SARS-COV-2 also has a requirement for lipid in its viral life cycle given that inhibition of DGAT1, which is a key enzyme in the production of triacylglycerol synthesis, and underpins lipid droplet formation, reduced SARS-CoV-2 replication in vitro. Additionally, the data underpinning the statements that SARS-CoV-2 localises to and utilises lipid droplets as a replication platform, are not well supported by the limited imaging in the manuscript, and much work needs to be done to determine if indeed SARS-CoV-2 requires the lipid droplet as a platform for replication or assembly. Data investigating the longitudinal lipid droplet response may also assist in delineating the reliance of SARS-CoV-2 on lipid droplet’s as a replication platform, versus a ‘fuel’ source as is the case for flaviviruses.

This manuscript also demonstrates that SARS-CoV-2 replication in monocytes upregulates many inflammatory cytokines, and that inhibition of lipid droplet formation with the use of DGAT1 inhibitors was able to reduce this increase and lessen cell death in vitro. However, the experiments are not well controlled, with no data presented for use of the DGAT1 inhibitor alone, in the context of no infection. Additionally, caution needs to be observed when interpreting the data, not only due to the lack of all controls, but also in light of the fact that the DGAT1 inhibitor also lessens viral replication, making it difficult to determine if it is the reduction in lipid droplets that results in the lowered inflammatory cytokine levels, or the reduction in viral replication; especially as replication data is not given for these experiments.

This study is well written and integrative of the literature in the field. It represents numerous interesting findings in the context of SARS-CoV-2 and the ability of lipid droplets to affect the replication of the virus, and the production of inflammatory mediators. It will serve as a good preliminary set of data to underpin more extensive studies to truly delineate the role of these organelles, and DGAT1 in the life cycle of SARS-CoV-2.

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