Elevated circulating monocytes and monocyte activation in COVID-19 convalescent individuals, 2023, Park et al.

SNT Gatchaman · Apr 20, 2023

Elevated circulating monocytes and monocyte activation in COVID-19 convalescent individuals
Park, Juwon; Dean, Logan S.; Jiyarom, Boonyanudh; Gangcuangco, Louie Mar; Shah, Parthav; Awamura, Thomas; Ching, Lauren L.; Nerurkar, Vivek R.; Chow, Dominic C.; Igno, Fritzie; Shikuma, Cecilia M.; Devendra, Gehan

Background
Monocytes and macrophages play a pivotal role in inflammation during acute SARS-CoV-2 infection. However, their contribution to the development of post-acute sequelae of SARS-CoV-2 infection (PASC) are not fully elucidated.

Methods
A cross-sectional study was conducted comparing plasma cytokine and monocyte levels among three groups: participants with pulmonary PASC (PPASC) with a reduced predicted diffusing capacity for carbon monoxide [DLCOc, <80%; (PG)]; fully recovered from SARS-CoV-2 with no residual symptoms (recovered group, RG); and negative for SARS-CoV-2 (negative group, NG).

The expressions of cytokines were measured in plasma of study cohort by Luminex assay. The percentages and numbers of monocyte subsets (classical, intermediate, and non-classical monocytes) and monocyte activation (defined by CD169 expression) were analyzed using flow cytometry analysis of peripheral blood mononuclear cells.

Results
Plasma IL-1Ra levels were elevated but FGF levels were reduced in PG compared to NG. Circulating monocytes and three subsets were significantly higher in PG and RG compared to NG. PG and RG exhibited higher levels of CD169+ monocyte counts and higher CD169 expression was detected in intermediate and non-classical monocytes from RG and PG than that found in NG.

Further correlation analysis with CD169+ monocyte subsets revealed that CD169+ intermediate monocytes negatively correlated with DLCOc%, and CD169+ non-classical monocytes positively correlated with IL-1a, IL-1b, MIP-1a, Eotaxin, and IFN-g.

Conclusion
This study present evidence that COVID convalescents exhibit monocyte alteration beyond the acute COVID-19 infection period even in convalescents with no residual symptoms. Further, the results suggest that monocyte alteration and increased activated monocyte subsets may impact pulmonary function in COVID-19 convalescents. This observation will aid in understanding the immunopathologic feature of pulmonary PASC development, resolution, and subsequent therapeutic interventions.

Link | PDF (Frontiers in Immunology)

Hutan · Apr 20, 2023

It's great that this study was very selective with the group with post-acute covid-19 symptoms i.e.

Abstract said: ↑

participants with pulmonary PASC (PPASC) with a reduced predicted diffusing capacity for carbon monoxide [DLCOc, <80%; (PG)]
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They didn't just use a group of people with Long Covid, with that vaguely defined as at least one ongoing symptom, which could be anything as diverse as loss of smell, poorer lung function and ME/CFS.

It doesn't sound as though they were able to distinguish the monocytes of people fully recovered from Covid-19 (i.e. with no residual symptoms) from people with residual pulmonary symptoms. Nevertheless, the monocytes of both of these groups looked different to those of people who had not had a Covid-19 infection. Therefore, the results from this study will provide a useful comparison for data from people with post-Covid-19 ME/CFS.

It would have been good to see some indication in the abstract of the length of time after the infection that samples were taken, and the actual stats for the differences.

Hutan · Apr 20, 2023

Background on CD169+ from
Functions of CD169 positive macrophages in human diseases (Review), 2021

CD169+ macrophages are a unique type of macrophage subset that differ from M1 and M2 macrophages. CD169+ macrophages are present in multiple tissues and organs throughout the body and are primarily expressed in secondary lymphoid organs.

Unlike M1 and M2 macrophages, CD169+ macrophages can interact directly with T cells, B cells and dendritic cells (DC) through CD169 molecules to participate in immune regulation

CD169, is a member of the Siglec family (9). It is primarily expressed on the surface of specific macrophage subsets and its precursor monocytes, as well as on some DCs or T lymphocytes

CD169 is involved in cell-to-cell adhesion and cell-pathogen interactions (12). The CD169 molecule endows CD169+ macrophages with their unique functions. Cells expressing CD169 have high affinity for α2-3-glycosyltransferase and glucosidase, and communicate with other immune cells by recognizing and binding other cell surface polysaccharides, such as CD43 on T cells (13). CD169+ macrophages in the marginal zone of the spleen recognize phosphatidylserine on the surface of apoptotic cells, present apoptotic cell antigens and recruit regulatory T cells (Tregs) to exhibit their role in immune tolerance (14). Furthermore, the recruitment of Tregs may negatively regulate the immune responses and inhibit autoimmune diseases

The development of CD169+ macrophages also depends on lymphotoxin (LT)-α and LT-β secreted by B cells, and the deletion of B cells or LT can affect cell development directly (29,30). In the colon however, the development of CD169+ macrophages is dependent on vitamin A, rather than LT (26). Colonic CD169+ macrophages display different phenotypes, which is dependent on Maf expression levels in various phases of inflammation (31). Moreover, CD169 expression in the peripheral blood can be induced by type I interferon (IFN) in vitro, and both type I IFN levels and the expression of CD169 is increased in animal models and patients with autoimmune diseases

CD169+ macrophages are reported to be the primary cell type infected during viral infection, and they can capture viral particles in the blood, absorb antigens, such as immune complexes and viruses, and then present them in a complete form to follicular B cells, inducing germinal centre B cellular responses. CD169+ macrophages have been shown to enforce viral replication, resulting in the delivery of a large number of viral antigens, and the amplification of T and B lymphocyte responses

Type I IFN induced macrophages express CD169 molecules both in vivo and in vitro (50). CD169+ macrophages can also mediate antiviral activity by secreting type I IFN during viral infection. Since CD169+ macrophages simultaneously express programmed death ligands (PD-L1), the expression of IFN-I can upregulate the expression of PD-L1, which may result in CD8+ T cell exhaustion. The exhaustion of CD8+ T cells is a double-edged sword. In studies of lymphocytic choroidal meningitis virus infection in vivo, the persistent expression of IFN-I resulted in increased IL-10 and PD-L1 levels (79). IFN-I produced by CD169+ macrophages during chronic infection inhibits activation of the immune response to secondary infection (80). However, the absence of CD169+ macrophages results in inadequate production of IFN-I, reducing antiviral activity and persistence of the virus in the human body.
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Hutan · Apr 20, 2023

From a recent paper specifically looking at people with post-Covid exertion intolerance, a finding of increased numbers of CD169+ macrophages:

SNT Gatchaman said: ↑

We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages.
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But, this latest study might indicate that a persisting increase in CD169+ macrophages is a general post-Covid effect. It's great that Maureen Hanson's group will be looking more into monocytes (macrophage precursors) in ME/CFS.

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Elevated circulating monocytes and monocyte activation in COVID-19 convalescent individuals, 2023, Park et al.

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Elevated circulating monocytes and monocyte activation in COVID-19 convalescent individuals, 2023, Park et al.

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