Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post‐acute sequelae of COVID‐19

Abstract

Post‐acute sequelae of COVID‐19 (PASC) are long‐term consequences of SARS‐CoV‐2 infection that can substantially impair the quality of life. Underlying mechanisms ranging from persistent viruses to innate and adaptive immune dysregulation have been discussed. Here, we profiled the 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 a potential biomarker for persistent viral reservoirs. At a median time of 8 months after infection, we found pronounced dysregulation in almost all tested soluble factors, including both pro‐inflammatory and pro‐fibrotic cytokines. These immunological perturbations were remarkably independent of ongoing PASC symptoms per se, but further correlation and regression analyses suggested PASC‐specific patterns involving CCL2/MCP‐1 and IL‐8 that either correlated with sCD162, sCD206/MMR, IFN‐α2, IL‐17A and IL‐33, or IL‐18 and IL‐23. 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. These data confirm prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrate its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes.

High number of SARS-CoV-2 persistent infections uncovered through genetic analysis of samples from a large community-based surveillance study

“…Intriguingly, individuals with persistent infections report fewer symptoms later in a persistent infection compared to at their first positive sample, or remain asymptomatic throughout infection, but have more than 50% higher odds of Long Covid compared to a control group. Although the link between viral persistence and Long Covid may not be causal, these results suggest persistent infections could be contributing to the pathophysiology of Long Covid 10,38 , as also evidenced by the observation of circulating SARS-CoV-2 S1 spike protein in a subset of patients with Long Covid months after first infection 39 . The association between persistent infection and Long Covid does not imply that every persistent infection can lead to Long Covid, only 9% of persistently infected individuals reported having Long Covid, nor does it mean that all cases of Long Covid are due to a persistent infection.…”

Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling

“…Such observations further suggest the involvement of epigenetic regulatory mechanisms in COVID-19 [ 90 ]. MCP-1, a pro-inflammatory chemokine well-known to be increased in COVID-19 patients [ 91 , 92 , 93 , 94 , 95 ], was also found to be increased in SARS-CoV-2-exposed HBMEC conditioned media, as detected by mini-proteome assays. Accordingly, recent findings from our group show that both delta and D614G Spike1 proteins are capable of inducing MCP-1 release from HBMECs (Stangis and Toborek et al, unpublished data).…”

COVID-19, post-acute COVID-19 syndrome (PACS, “long COVID”) and post-COVID-19 vaccination syndrome (PCVS, “post-COVIDvac-syndrome”): Similarities and differences

“…(a) Spike protein concentration in blood plasma in individuals with and without PACS. Reprinted and modified from Schultheiß et al [403] , with permission from the publisher. (b) Time-dependent spike and nucleocapsid protein concentration in blood plasma in individuals with PACS and COVID-19.…”