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

[Andy]

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

 

[CRG]

Study population average age =60, male:female 1.76:1, high levels of overweight and pre infection morbidity.

 

[Hutan]

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.

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.

 

[Dolphin]

Press release:
https://www.manchester.ac.uk/discov...behaviour-could-be-drug-target-in-long-covid/

 

[SNT Gatchaman]

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

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

This work provides an important contribution to the growing body of evidence that long COVID is a multifarious disease with diverse causes.

The message of studies such as this is also one of hope for those who have suffered for many years from mysterious and hard to manage conditions termed variously post-viral fatigue, fibromyalgia, autonomic instability and other conditions that may be disabling but for which no underlying cause or treatment is evident. If the COVID-19 pandemic ultimately leads to a better understanding of what causes such ailments and how they might be treated, many will have cause to celebrate.

 

[Hutan]

From the editorial:

With respect to the diversity of long COVID syndromes, Scott et al. [9] distinguish patients presenting with fatigue from those suffering from breathlessness. They demonstrated that individuals with fatigue exhibited persistently low monocyte expression of COX-2 and CXCR2 up to 9 months after COVID-19. COX-2 is a prostaglandin-producing enzyme involved in the eicosanoid pathway which is known to be important in maintaining tissue integrity, platelet function and innate immune responses against pathogens [12, 13]. Thus, Scott et al. [9] make a case for localised lung injury in post-COVID-19 breathlessness, whilst more generalised inflammation involving monocytes and tissue macrophages might drive fatigue.

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.)

The protein encoded by this gene is a member of the G-protein-coupled receptor family. This protein is a receptor for interleukin 8 (IL8). It binds to IL8 with high affinity, and transduces the signal through a G-protein activated second messenger system.
This receptor mediates neutrophil migration to sites of inflammation. The angiogenic effects of IL8 in intestinal microvascular endothelial cells are found to be mediated by this receptor.

Viral persistence has been proposed as a potential mechanism for ongoing immune perturbation in many post-viral syndromes, and demonstrated after Ebola virus infection [17]. One study of 87 individuals found continued evolution of the B-cell response to SARS-CoV-2 up to 6 months after infection when 44% had persistent symptoms [18]. In this study, viral antigen was detected in intestinal biopsies 4 months after infection, providing evidence that persistent virus may stimulate chronic immune disturbance after COVID-19. With this in mind, it is interesting that Scott et al. [9] found enhanced monocyte expression of the gut-homing integrin β7 in patients with acute severe COVID-19, highlighting the possibility that an intestinal coronaviral reservoir might be driving persistent inflammation. Persistent virus has also been found in the lung up to 300 days after SARS-CoV-2 infection [19], which might explain ongoing lung inflammation described by Scott et al. [9]. Alternatively, reactivation of latent Epstein–Barr virus (or cytomegalovirus) infection might conceivably result in inflammatory responses in certain patients, as suggested by two studies of patients with persistent fatigue and/or neurological symptoms such as brain fog [20, 21]. Future studies which confirm or refute viral persistence or reactivation as a potential cause could be transformative, should trials of antivirals be shown to clear virus and resolve persistent symptoms.

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?

 

[Hutan]

Interesting, on the low expression of CXCR2:

Distinguishing Sepsis From Infection by Neutrophil Dysfunction: A Promising Role of CXCR2 Surface Level, 2020

Our study found that, among neutrophil functions studied, only CXCR2 surface level is associated with sepsis. At disease onset, CXCR2 level decrease, with a dose-response relationship with clinical severity. Its level reverts to resemble infected patients by the end of the week.

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.

Previous experimental studies have demonstrated reduced CXCR2 surface level due to CXCR2 receptor internalization induced by circulating chemokines (15, 23). The lack of CXCR2 surface receptors was also linked to severe neutrophil hyperplasia in the bone marrow and neutrophilia in sepsis mice model

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.

Based on our observation, abnormal neutrophil migration due to decreased CXCR2 surface receptors should be considered the immunopathological feature, which could act as a marker for distinguishing sepsis from infected patients at the onset of the disease. As a consequence of decreased CXCR2 surface level, appropriate neutrophil chemotaxis was disrupted, causing inappropriate extravasation of neutrophils into various organs. Tissue injury inflicted by this process leads to multiorgan failure (15); which is the salient clinical feature that differentiates sepsis from infection by Sepsis-3 definition (1).

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.

 

[chillier]

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:

bulk RNA-seq of monocytes:


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.

 

[SNT Gatchaman]

See also Epigenetic memory of coronavirus infection in innate immune cells and their progenitors (2023)