Lipid droplets - have they been investigated in ME? Should they be?

[Ravn]

The existence of lipid droplets in cells is nothing new. But it now seems they could have more functions than previously thought: they may play key roles in innate immune response and in regulating cell metabolism.

The only search result I got for 'lipid droplets + ME?CFS' is this 2017 presentation by Naviaux about Dauer in C.elegans. So unless I missed something this hasn't been a major line of enquiry in ME. Should it be? Or unlikely to be relevant?

https://d1qwuymb7uy402.cloudfront.n.../05/Naviaux-CFS-For-CDC-Talk-5-25-17v3s-2.pdf

The following two papers have nothing to do with ME but are basic science investigations into lipid droplet function in response to bacterial and viral infections (my paragraph breaks).

Cells drop a bomb on pathogens

Lipid droplets (LDs) accumulate in cells to serve as lipid storage organelles. They are also an attractive source of nutrients for many pathogens. Bosch et al. show that various proteins involved in innate immunity form complexes on LDs in response to bacterial lipopolysaccharide (see the Perspective by Green).

Upon activation, LDs became physically uncoupled from mitochondria, driving a shift in cells from oxidative phosphorylation to aerobic glycolysis.

This work highlights the ability of LDs both to kill pathogens directly and to establish a metabolic environment conducive to host defense. This may inform future antimicrobial strategies in the age of antibiotic resistance.

[...]
Conclusion

These results demonstrate that LDs form a first-line intracellular defense. They act as a molecular switch in innate immunity, responding to danger signals by both reprogramming cell metabolism and eliciting protein-mediated antimicrobial mechanisms.

Mechanisms of LD trafficking and docking with phagocytic and parasitophorous membranes, observed here and described for several pathogens, may facilitate the delivery of immune proteins located on the LD surface.

Intracellular LDs can provide infected cells with several biological benefits, serving as a location to attract pathogens as well as coordinating different immune systems that operate simultaneously against different classes of pathogens.

LDs may also sequester cytotoxic compounds (such as antimicrobial peptides), reducing damage to other cellular organelles [...]

Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense
Marta Bosch et al. Science,16 Oct 2020
https://science.sciencemag.org/content/370/6514/eaay8085

Lipid droplets (LDs) are increasingly recognized as critical organelles in signalling events, transient protein sequestration and inter-organelle interactions. However, the role LDs play in antiviral innate immune pathways remains unknown.

Here we demonstrate that induction of LDs occurs as early as 2 hours post viral infection, is transient, and returns to basal levels by 72 hours. This phenomenon occurred following viral infections, both in vitro and in vivo.

Virally driven LD induction was type-I interferon (IFN) independent, however, was dependent on EGFR engagement, offering an alternate mechanism of LD induction in comparison to our traditional understanding of their biogenesis.

Additionally, LD induction corresponded with enhanced cellular type-I and -III IFN production in infected cells, with enhanced LD accumulation decreasing viral replication of both HSV-1 and Zika virus (ZIKV).

Here, we demonstrate for the first time, that LDs play vital roles in facilitating the magnitude of the early antiviral immune response specifically through the enhanced modulation of IFN following viral infection, and control of viral replication.

By identifying LDs as a critical signalling organelle, this data represents a paradigm shift in our understanding of the molecular mechanisms which coordinate an effective antiviral response.

(Preprint) Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response
EA Monson, KM Crosse, M Duan, W Chen, RD O’Shea, LM Wakim, DR Whelan, KJ Helbig
bioRxiv 2020.02.12.946749; doi: https://doi.org/10.1101/2020.02.12.946749
https://www.biorxiv.org/content/10.1101/2020.02.12.946749v1

 

[Hutan]

It's new stuff on the immune responses - those two papers in @Ravn's post are 2020 ones. The following New Scientist article (also very recent - 15 Oct) is a readable account of lipid droplets:
Read more: https://www.newscientist.com/articl...e-proteins-to-fight-infections/#ixzz6bmRzQVva

In a series of experiments on mice and on human cells, Parton’s team found that lipid droplets carry an array of proteins that are involved in the immune response. When dangerous bacteria enter the cell, chemical alarm signals are released, and these activate the immune proteins on the lipid droplets – which kill any bacteria that approach the droplet.

The cell has taken one of its most vulnerable components and weaponised it, says Parton. “It’s using it like a honey trap,” he says. “It’s producing these proteins, putting them on the lipid droplets, and then killing the bacteria.”

The evidence so far only shows that the lipid droplets can fight bacteria – there is no sign of them fighting viruses.

The researchers involved in that work thought the lipid droplets helped kill some bacteria, not viruses. Whereas the Monson et al paper was looking at anti-virus mechanisms.

From the New Scientist article:
“We now have whole conferences looking just at the lipid droplets and all the associated processes.”

 

[Ravn]

From the New Scientist article:
“We now have whole conferences looking just at the lipid droplets and all the associated processes.”

There's even a glimmer of hope we may, eventually and indirectly, learn more about the role of lipid droplets in ME. Their role in active Covid19 has caught the eye of researchers. With any luck this will lead to some of them looking into their role in long Covid, and with a great deal of luck this might tell us something about ME.

Lipid droplets fuel SARS-CoV-2 replication and production of inflammatory mediators (my bolding and line breaks)

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 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 modulates pathways of lipid synthesis and uptake, including CD36, SREBP-1, PPARγ and DGAT-1 in 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 in infected cells.

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.

Suelen da Silva Gomes Dias et al.
(preprint) bioRxiv 2020.08.22.262733; doi: https://doi.org/10.1101/2020.08.22.262733

 

[Mithriel]

I may be reading it wrong, but if they help fight infections and help aerobic metabolism a virus that could switch them off, or an enterovirus that replicates to fill the cell but carries on living there instead of bursting the cell wall might cause a problem with aerobic respiration... ME! (not scientific !!!)