[Preprint] Liquid biomarkers of macrophage dysregulation & circulating spike protein illustrate the biological heterogeneity in patients with LC, 2022

[SNT Gatchaman]

Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19
Christoph Schultheiss, Edith Willscher, Lisa Paschold, Cornelia Gottschick, Bianca Klee, Lidia Bosurgi, Jochen Dutzmann, Daniel Sedding, Thomas Frese, Matthias Girndt, Jessica I. Hoell, Michael Gekle, Rafael Mikolajczyk, Mascha Binder

Post-acute sequelae of COVID-19 (PASC) are long-term consequences of SARS-CoV-2 infection that can substantially impair quality of life. Underlying mechanisms ranging from persistent virus to innate and adaptive immune dysregulation have been discussed.

Here, we profiled plasma of 181 individuals from the cohort study for digital health research in Germany (DigiHero) including individuals after mild to moderate COVID-19 with or without PASC and uninfected controls. We focused on soluble factors related to monocyte/macrophage biology and on circulating SARS-CoV-2 spike (S1) protein as potential biomarker for persistent viral reservoirs.

At a median time of eight months after infection, we found pronounced dysregulation in almost all tested soluble factors including both pro-inflammatory and pro-fibrotic cytokines. These perturbations were remarkably independent of ongoing symptoms, but further correlation and regression analyses suggested PASC specific patterns involving CCL2/MCP-1 and IL-8 as well as long-term persistence of high IL-5 and IL-17F levels. None of the analyzed factors correlated with the detectability or levels of circulating S1 indicating that this represents an independent subset of patients with PASC.

This data confirms prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrates its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes.

Link | PDF (MedXriv)

 

[SNT Gatchaman]

Sampling blood ("liquid biopsy") offers limited insight, but the authors are suggesting at least two sub-groups of long COVID. They suggest one group is due to monocyte/macrophage dysregulation and another due to viral (antigen) persistence.

We recently reported persisting elevation of a triad of monocyte/macrophage-related cytokines - IL-1β, IL-6 and TNF 8-10 months after SARS-CoV-2 infection in patients with PASC. We hypothesized that these cytokines are secreted by tissue-resident macrophages that engage into a self-sustaining proinflammatory loop that may fuel PASC. Such macrophage imprinting has been previously reported to be potentially induced through engulfment of spike protein by tissue-resident macrophage in early disease phases.

Our data illustrate the pronounced dysregulation of monocyte/macrophage-related soluble factors in some individuals with PASC and the long-term circulation of spike protein in others. Together, this data further refines the molecular underpinnings of PASC and suggests the existence of different PASC subtypes.

We observed markedly increased plasma levels of IL-5, IL-9, IL-17F, IL-18, IL-22, IL-23, IL-33, CCL2/MCP-1 and sCD163

This analysis revealed a characteristic pattern of correlating cytokines in post-COVID-19 samples relatively independent of PASC, but not in uninfected individuals.

Persistent immunogenic viral antigens like the SARS-CoV-2 S1 spike protein are potential drivers of PASC that might also fuel systemic cytokine and chemokine perturbations. To study this hypothesis, we profiled our cohort for levels of circulating S1. Since the S1 antigen has been detected in plasma after vaccination, we restricted this analysis to individuals without prior vaccination. Around 35% of individuals with prior COVID-19 but no PASC showed measurable levels of circulating S1 protein. In the ongoing PASC group, circulating S1 was detected in around 64% of individuals. This group also showed numerically higher circulating S1 levels as compared to individuals without PASC. However, the detectability or level of circulating S1 did not show a clear correlation with any of the soluble factors dysregulated in individuals with ongoing PASC.

While the soluble “immune” factors showed strong correlations with each other, we did not find a strong correlation with the detectability or level of circulating S1. This was a relevant finding that we interpreted as indicative of distinct subgroups of PASC that may result from divergent underlying mechanisms. Unfortunately, the presumable PASC subsets suggested by our analyzes – individuals with predominant macrophage dysregulation versus individuals with persistent viral proteins or reservoirs – were rather small subgroups.

 

[John Mac]

Medical Xpress article on the study
Long COVID study: Blood values indicate reprogramming of immune cells
by Jonas Machner, University Medicine Halle

The underlying mechanisms of long COVID are not yet fully understood. Molecular clues to different subgroups of long COVID have now been provided by a research group at University Medicine Halle.

When symptoms persist: After recovering from a COVID-19 infection, many people suffer from a secondary disease called long COVID or post-COVID syndrome. A research group at University Medicine Halle has discovered molecular evidence for various long COVID subtypes. Patterns occur that could provide a potential therapeutic approach.

The data suggest that various mechanisms lead to the development of the syndrome, including a "reprogramming" of immune cells. All of the participants were recruited through "DigiHero," a Germany-wide study on digital health research conducted by University Medicine Halle. The results were recently published in the Journal of Medical Virology.

https://medicalxpress.com/news/2023-01-covid-blood-values-reprogramming-immune.html