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Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID 2023 Scott et al

Discussion in 'Long Covid research' started by Andy, Mar 17, 2023.

  1. Andy

    Andy Committee Member

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    Abstract

    Background
    COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID).

    Methods
    We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalization and up to 9 months of convalescence following COVID-19, respiratory syncytial virus (RSV) or influenza A (flu). Progressive fibrosing interstitial lung disease (PFILD) patients were included a positive control for severe, ongoing lung injury.

    Results
    Monocyte alterations in acute COVID-19 patients included aberrant expression of leucocyte migration molecules, continuing into convalescence (n=142) and corresponding to specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of chemokine receptor CXCR6 (p<0.0001) and adhesion molecule PSGL-1 (p<0.01), alongside preferential migration of monocytes towards CXCR6 ligand CXCL16 (p<0.05) which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in PFILD patients (p<0.001) confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited sustained reduction of the prostaglandin-generating enzyme COX-2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in RSV or flu convalescence.

    Conclusions
    Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.

    Open access, https://erj.ersjournals.com/content/early/2023/02/23/13993003.02226-2022
     
    Ash, Robert 1973, Hutan and 1 other person like this.
  2. CRG

    CRG Senior Member (Voting Rights)

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    Study population average age =60, male:female 1.76:1, high levels of overweight and pre infection morbidity.
     
    EndME, Dolphin, Hutan and 1 other person like this.
  3. Hutan

    Hutan Moderator Staff Member

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    We've seen prostaglandins mentioned recently in this paper:
    An airway-to-brain sensory pathway mediates influenza-induced sickness 2023 Bin et al
    However that paper reported that prostaglandins produce the sickness response (which shares a number of the symptoms of
    post-viral fatigue syndrome/MECFS) - and the abstract of this one seems to suggest the opposite in a post-viral fatigue syndrome. In that earlier thread, we noted how COX-2 inhibiting drugs such as nurofen seem to help with ME/CFS symptoms. But here, the suggestion seems to be that COX-2 is already reduced in ME/CFS-like Long Covid.

    I'm intrigued to read this new paper, to see how solid that finding is, and to see if there is any possible explanation for the different results of the two papers.
     
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  4. Dolphin

    Dolphin Senior Member (Voting Rights)

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  5. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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    Formal link https://erj.ersjournals.com/content/61/5/2202226 (also open access)

    Discussed in editorial: Long COVID: clues about causes (May 2023, ERJ)

     
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  6. Hutan

    Hutan Moderator Staff Member

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    From the editorial:

    Individuals with fatigue have low monocyte expression of COX-2 and CXCR2
    CXCR2 is a protein that is a receptor for IL-8, also known as CD182.
    (How interesting, although probably irrelevant, CXCR2 is enormously expressed in the appendix, substantially more than other tissues. Also in the spleen and oesophagus. That's the strongest indication I have seen that the appendix has a purpose.)

    We desperately need more studies addressing this question - is the SARS-CoV-2 virus persisting or activating latent viruses, and can anti-virals eliminate viruses and improve symptoms?
     
    Last edited: Jun 2, 2023
    Ash, Wyva, Peter Trewhitt and 2 others like this.
  7. Hutan

    Hutan Moderator Staff Member

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    Interesting, on the low expression of CXCR2:

    Distinguishing Sepsis From Infection by Neutrophil Dysfunction: A Promising Role of CXCR2 Surface Level, 2020
    Neutrophils aren't the same as monocytes (the cell type that the study that is the subject of this thread found had low CXCR2 expression), but they have similar functions. I think it has been suggested that the metabolite profile of ME/CFS had similarities with the profile of sepsis.

    In the sepsis study, increased numbers of neutrophils with no CXCR2 at disease onset was associated with subsequent death. Patients with just an infection and without sepsis had higher levels of CXCR2, approaching healthy levels.

    They are saying that CXCR2 surface receptors decrease when there is a lot of neutrophil production (in the bone marrow) and a lot of neutrophils in the blood.

    And the sepsis paper is saying that the lack of the receptors results in the neutrophils getting lost or going haywire and ending up in organs, where they cause damage - which is what sepsis is. How this might relate to the 'long COVID with fatigue' subset, I don't know.
     
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  8. chillier

    chillier Senior Member (Voting Rights)

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    Just checking to see if they see these genes in Ahmed & Grimson 2022's single cell RNA seq paper where they find some monocyte abnormalities in ME/CFS and then validate with RNA seq of bulk sorted monocytes.

    monocyte chemokine related expression from scRNA-seq:
    upload_2023-6-2_11-43-1.png
    bulk RNA-seq of monocytes:
    upload_2023-6-2_11-44-14.png

    Both CCL4 and CXCR4 appear in both of their datasets, but no sign of CXCR2 or 6 or COX2 in their data for ME/CFS.
     
    Last edited: Jun 2, 2023
    FMMM1, Hutan, Peter Trewhitt and 2 others like this.
  9. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

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