Unique molecular signatures sustained in circulating monocytes and regulatory T cells in Convalescent COVID-19 patients

Abstract

Over two years into the COVID-19 pandemic, the human immune response to SARS-CoV-2 during the active disease phase has been extensively studied. However, the long-term impact after recovery, which is critical to advance our understanding SARS-CoV-2 and COVID-19-associated long-term complications, remains largely unknown. Herein, we characterized multi-omic single-cell profiles of circulating immune cells in the peripheral blood of 100 patients, including covenlesent COVID-19 and sero-negative controls. The reduced frequencies of both short-lived monocytes and long-lived regulatory T (Treg) cells are significantly associated with the patients recovered from severe COVID-19. Consistently, sc-RNA seq analysis reveals seven heterogeneous clusters of monocytes (M0-M6) and ten Treg clusters (T0-T9) featuring distinct molecular signatures and associated with COVID-19 severity. Asymptomatic patients contain the most abundant clusters of monocyte and Treg expressing high CD74 or IFN-responsive genes. In contrast, the patients recovered from a severe disease have shown two dominant inflammatory monocyte clusters with S100 family genes: S100A8 & A9 with high HLA-I whereas S100A4 & A6 with high HLA-II genes, a specific non-classical monocyte cluster with distinct IFITM family genes, and a unique TGF-b; high Treg Cluster. The outpatients and seronegative controls share most of the monocyte and Treg clusters patterns with high expression of HLA genes. Surprisingly, while presumably short-ived monocytes appear to have sustained alterations over 4 months, the decreased frequencies of long-lived Tregs (high HLA-DRA and S100A6) in the outpatients restore over the tested convalescent time (>= 4 months). Collectively, our study identifies sustained and dynamically altered monocytes and Treg clusters with distinct molecular signatures after recovery, associated with COVID-19 severity.

A scoping review of regulatory T cell dynamics in convalescent COVID-19 patients – Implications for Long COVID?

“…Those subjects exhibited a higher Treg frequency than severely ill who were categorized as having high CD8 + T cell counts (>250/ml) and patients with mild initial disease (63). Two other studies that investigated total Treg frequencies documented both higher and lower proportions in convalescent outpatients compared to those who were hospitalized (51, 59) (Figure 3). Similarly as heterogeneous were the results of the studies that investigated Treg subsets.…”

“…The trend towards a quantitative reconstitution of Tregs was supported by five studies investigating patients recovering from diseases of different severity (51,52,54,55,59). The fact that the studies were not able to find significant differences in Treg frequency between recovering subjects and seronegative controls suggests that the peripheral Treg population was either unaffected by the initial disease or returned to normal values within the first six weeks following mild disease (54,55,59) or four months following severe disease (51,59).…”

“…The comparison between recovered patients and seronegative controls produced ambiguous results. While five studies found no significant difference in frequencies of total Tregs between patients post-COVID-19 and patients without history of COVID-19 (51, 52, 54, 55, 59), two studies reported a lower (53, 60) and four reported a greater peripheral Treg frequency in recovered patients (50, 57, 61, 62) (Figure 3). However, this discrepancy did not seem to be attributable to differences in initial disease severity or the time elapsed since diagnosis.…”

“…Five studies compared Treg outcomes among recovered patients with different initial disease severities, reaching equivocal results (50, 51, 57, 59, 63). A study that followed-up subjects that were hospitalized for mild and severe courses of COVID-19 found out that six months post-discharge there were patients with severe illness that presented with persistently low CD8 + T cell counts (<250/ml) (63).…”

Cigarette Smoke and Morphine Promote Treg Plasticity to Th17 via Enhancing Trained Immunity

“…Under normal conditions, Foxp3 + Tregs migrate into inflamed tissues to suppress inflammatory responses to exert immunosuppressive effects and accelerate tissue repair [ 15 , 138 ]. In pre-existing respiratory comorbidities such as COVID-19, which leads to the disruption of the immune system, exacerbated inflammation which is partly due to the decreased expression of Tregs or defects in these cells results in weakening the Tregs effects of inflammatory inhibition, causing an imbalance in Treg/Th17 ratio, and increasing the risk of respiratory failure [ 137 , 139 , 140 , 141 ]. Since our data showed that the smoke and morphine combination promote weakened, plastic/dysfunctional Tregs and Treg plasticity toward Th17 cells, smoke plus morphine in combination in pre-existing respiratory co-morbidities such as COVID-19 will exacerbate inflammation and increase the severity of the disease.…”