Long-lasting Immune Alterations in COVID-19 Patients: Implications for Post-Acute Sequelae and Therapeutic Approaches


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.

The NF-κB pathway’s activation appears specific to SARS-CoV-2 infection and may play a central role in the prolonged pro-inflammatory response.

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.

This suggests that a continuous inflammatory stimulus or long-lived pro-inflammatory cytokines in the extracellular matrix could contribute to these alterations.

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



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