The COVID-19 pandemic has triggered a global scientific response aimed at unraveling the complexities of the immune response to SARS-CoV-2 infection and its impact on clinical symptoms. While significant progress has been made in understanding the initial phases of the disease, the long-term consequences, including Post-Acute Sequelae of COVID-19 (PASC), remain elusive.
PASC is of particular concern due to the persistent infection rates and the threat of emerging variants. Recent advances in single-cell transcriptomics have facilitated the investigation of immune responses during both the acute and post-acute phases of COVID-19.
A Novel Perspective on Immune Alterations: Low-Dose IL-2 Immunotherapy
An intriguing development in understanding immune responses comes from the study of low-dose interleukin-2 (IL-2) immunotherapy in newly diagnosed type 1 diabetes (T1D) patients.
This approach revealed a prolonged anti-inflammatory gene expression signature known as the IL2-AIS, even after Treg (regulatory T cell) frequencies returned to baseline. Unexpectedly, this signature demonstrated a shift towards an anti-inflammatory lymphoid environment. Genes such as CISH (negative regulator of cytokine signaling) and TNF-inducible genes played crucial roles in this signature.
Connecting the Dots: IL2-AIS in COVID-19 Patients
Several genes constituting the IL2-AIS, including CISH, AREG, DUSP2, NFKBIA, and TNFAIP3, have shown differential expression in COVID-19 patients. However, the extent and dynamics of these changes remain unclear. Leveraging single-cell transcriptomic data from large COVID-19 cohorts, including the Oxford COVID-19 Multi-omics Blood Atlas (COMBAT) and INCOV cohorts, we have identified a core set of co-regulated genes from the IL2-AIS that exhibit opposite expression patterns in COVID-19 patients’ T cells, B cells, NK cells, and monocytes. These pro-inflammatory alterations are progressively induced after symptom onset and persist for at least two months.
The Role of NF-κB: A Key Player in COVID-19 Immune Alterations
A noteworthy finding is the involvement of the NF-κB signaling pathway, consistent with its role in severe COVID-19.
Genes such as NFKBIA, NFKBIZ, FOS, JUN, TNFAIP3, RELB, NR4A2, DUSP1, and CD69 show upregulation in response to SARS-CoV-2 infection. This aligns with the pro-inflammatory environment seen in COVID-19 patients, as opposed to the stronger type I interferon response observed in influenza patients.
Mechanisms Underlying Long-lasting Alterations
The exact mechanisms behind these transcriptional changes are still unclear. It is plausible that cytokines produced during the acute phase of COVID-19 have extended biological activity in tissues, possibly due to binding to the extracellular matrix. Such prolonged immune alterations have been observed in mild COVID-19 patients, where pro-inflammatory responses persisted in monocyte-derived macrophages for months.
Implications for PASC and Therapeutic Approaches
The longevity of these transcriptional alterations raises concerns about the development of PASC. Understanding the cumulative effect of multiple SARS-CoV-2 infections on this immune signature is crucial, given the increased risk of morbidity observed in reinfections.
Low-dose IL-2 immunotherapy, which has a safe record in other contexts, offers a potential avenue for reversing these prolonged immune alterations in convalescent COVID-19 patients. However, careful consideration of timing and patient selection is essential to avoid unwanted hyperactivation of the immune response. Further research, including retrospective analysis of PASC incidence in IL-2-treated cohorts, is necessary to validate this approach.
In summary, our study sheds light on the long-lasting immune alterations induced by SARS-CoV-2 infection, suggesting a heightened pro-inflammatory state that persists beyond the acute phase of COVID-19. The inverse gene expression pattern observed compared to low-dose IL-2 immunotherapy in T1D patients implies that interval dosing of low-dose IL-2 may promote a prolonged regulatory environment in COVID-19 recovery. This research underscores the importance of investigating the mechanistic alterations triggered by SARS-CoV-2 infection to mitigate long COVID-19 complications effectively.
REFERENCE LINK : https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-023-01227-x#Sec14