Preprint Proteomic and metabolomic profiling of plasma uncovers immune responses in patients with Long COVID-19, 2024, Wei et al

[forestglip]

Proteomic and metabolomic profiling of plasma uncovers immune responses in patients with Long COVID-19

Yulin Wei, Hongyan Gu, Jun Ma, Xiaojuan Mao, Bing Wang, Weiyan Wu, Shimin Yu, Jinyuan Wang, Huan Zhao, yanbin he

[Preprint]

Abstract
Long COVID is an often-debilitating condition with severe, multisystem symptoms that can persist for weeks or months and increase the risk of various diseases. Currently, there is a lack of diagnostic tools for Long COVID in clinical practice. Therefore, this study utilizes plasma proteomics and metabolomics technologies to understand the molecular profile and pathophysiological mechanisms of Long COVID, providing clinical evidence for the development of potential biomarkers.

This study included three age- and gender-matched cohorts: healthy controls (n=18), COVID-19 recovered patients (n=17), and Long COVID patients (n=15).

The proteomics results revealed significant differences in proteins between Long COVID-19 patients and COVID-19 recovered patients, with dysregulation mainly focused on pathways such as coagulation, platelets, complement cascade reactions, GPCR cell signal transduction, and substance transport, which can participate in regulating immune responses, inflammation, and tissue vascular repair.

Metabolomics results showed that Long COVID patients and COVID-19 recovered patients have similar metabolic disorders, mainly involving dysregulation in lipid metabolites and fatty acid metabolism, such as glycerophospholipids, sphingolipid metabolism, and arachidonic acid metabolism processes.

In summary, our study results indicate significant protein dysregulation and metabolic abnormalities in the plasma of Long COVID patients, leading to coagulation dysfunction, impaired energy metabolism, and chronic immune dysregulation, which are more pronounced than in COVID-19 recovered patients.

Link | PDF (Preprint) [Open Access]

 

[Hutan]

I like the introduction. I like that there are matched groups of Long Covid, recovered and healthy controls. Group sizes are small though.

The symptoms are a bit random. Numbers of the Long Covid group (total 15 people) with the following symptoms:
Smell and taste dysfunction 4
Fatigue 4
Exertion dyspnea 5
Muscular soreness 4
Cough 3
Loss of appetite 3
Nausea 1

As with so many of these studies, I doubt that the quality of the sample is good enough to warrant the subsequent application of technology and substantial effort. Can we really expect to find some clues when just looking at 15 people with that mixture of symptoms?

I'm not sure if the problem is me - am I always expecting the researchers to look for the ME/CFS symptom constellation? Is it better to approach the Long Covid question without imposing pre-existing syndrome ideas? But, even so, I don't see how researchers can expect to find answers from a cohort with e.g. 4 people with smell or taste dysfunction who may not have other symptoms, when combined with 12 people without smell or taste dysfunction.

 

[Jonathan Edwards]

Complement and arachidonic acid metabolism mentioned again.

 

[Hutan]

All that said (re my post), GNAI2 and TSP1 proteins do look to be different (both increased) in some of the LC cohort, compared to the other two cohorts, and so maybe are worth keeping in mind when looking at other 'omic studies.

 

[Hutan]

On TSP1 (thrombospondin-1, THBS1)
US: Annual ME/CFS Working Group Meetings from 2020. Stanford/OMF

Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the THBS1 gene.[5][6]

Thrombospondin 1 is a subunit of a disulfide-linked homotrimericprotein. This protein is an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein can bind to fibrinogen, fibronectin, laminin, collagens types V and VII and integrins alpha-V/beta-1. This protein has been shown to play roles in platelet aggregation, angiogenesis, and tumorigenesis.[7][8]

 

[SNT Gatchaman]

Complement and arachidonic acid metabolism mentioned again.

And also sphingolipid metabolisim.

 

[Sasha]

And also sphingolipid metabolisim.

I know zero about biology but I recognise this term and have the impression that someone was making a really big deal about it a few years ago. Ron Davis or someone in his wider group, maybe?

 

[Hutan]

GNAI2
googled snippets

GNAI2 is a G protein that participates in G protein-coupled receptor (GPCR) and non-GPCR signaling pathways. It couples to CXCR2, which governs neutrophil trafficking

Guanine nucleotide-binding protein G(i) alpha (Gi-alpha) inhibits adenylate cyclase, thus inhibiting the production of cAMP from ATP and ultimately decreasing the activity of cAMP-dependent protein kinase.

These data suggest that decreased levels of cAMP may cause very significant loss of NK cytotoxic function

Recently, cAMP has been pointed out as coordinator of key steps of resolution of inflammation. Here, we summarize the evidence for the role of cAMP at inducing important features of resolution of inflammation.

In addition to reduced cAMP production, other physiological effects of inhibiting adenylate cyclase include:

• Accelerated Na+/H+ exchange
• Activated K+ conductances
• Inhibited voltage-sensitive Ca2+ channels
• Biochemical and electrophysiological changes

 

[Murph]

I know zero about biology but I recognise this term and have the impression that someone was making a really big deal about it a few years ago. Ron Davis or someone in his wider group, maybe?

It may have been Naviaux 2017, Sphingolipid was among the strongest findings there :

Recently, cAMP has been pointed out as coordinator of key steps of resolution of inflammation

This idea also brings Naviaux's thinking to mind, with his theories about failure to wrap up the cell danger response. Seems he has coined the term "salugenesis" to describe returning to health.

Salugenesis is the automatic, evolutionarily conserved, ontogenetic sequence of molecular, cellular, organ system, and behavioral changes that is used by living systems to heal. It is a whole-body process that begins with mitochondria and the cell. The stages of salugenesis define a circle that is energy- and resource-consuming, genetically programmed, and environmentally responsive. Energy and metabolic resources are provided by mitochondrial and metabolic transformations that drive the cell danger response (CDR) and create the three phases of the healing cycle: Phase 1-Inflammation, Phase 2-Proliferation, and Phase 3-Differentiation.

Each phase requires a different mitochondrial phenotype. Without different mitochondria there can be no healing. The rise and fall of extracellular ATP (eATP) signaling is a key driver of the mitochondrial and metabolic reprogramming required to progress through the healing cycle. Sphingolipid and cholesterol-enriched membrane lipid rafts act as rheostats for tuning cellular sensitivity to purinergic signaling. Abnormal persistence of any phase of the CDR inhibits the healing cycle,

 

[Sasha]

Thanks, @Murph, well-found! I'm pretty sure that was it. I don't know how his theory is thought of, at this point.

 

[Jonathan Edwards]

Sphingomyelin is essential to coherent cell membrane structure.
It might even be the writing on the (inside) wall!

Choline, complement, lipid - there ought to be some way they make sense.

The only thing I am a bit sceptical about is linking this to 'resolution of inflammation'. Ninety nine percent of our immune defence involves non-inflammatory mechanisms like silent complex clearance and induced apoptosis. Danger signals can operate without inflammation.