Nikhil Prasad Fact checked by:Thailand Medical News Team Feb 24, 2024 8 months, 3 weeks, 6 days, 11 hours, 17 minutes ago
COVID-19 News: The aftermath of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, commonly known as COVID-19, has brought to light a perplexing phenomenon termed Long COVID. This condition as reported in past studies and
COVID-19 News reports, manifests as persistent symptoms lasting beyond 12 weeks post-infection, posing a significant challenge in terms of diagnosis, treatment, and understanding its underlying mechanisms. Researchers from the University of Cambridge in the United Kingdom have conducted a groundbreaking study shedding light on a potential immunological mechanism associated with Long COVID, focusing on the persistent release of interferon-γ (IFN-γ) by T cells.
Spontaneous IFN-γ production resolves in individuals with symptom resolution.
(A) Data were replotted for PBMCs from 10 donors who gave samples at 28 and 180 days after positive RT-qPCR result and reported symptom recovery. (B) IFN-γ release was measured by FluoroSpot assay for patients with Long Covid who did not report symptom resolution. Results are plotted at time after symptom onset. (A) and (B) IFN-γ release was quantified as spot forming units per million PBMCs. Each point represents the mean from a single donor, where donor samples were run in duplicate and zero results were set as 0.1 to allow their inclusion on a log scale. Significance calculated by or two-way Wilcoxon signed-rank test for (A) where **P < 0.01.
Defining Long Covid
Long COVID, also referred to as post-acute sequelae of SARS-CoV-2 (PASC) or post-COVID syndrome, presents a complex clinical challenge. It involves a range of relapsing and remitting symptoms with multisystemic organ involvement, affecting individuals irrespective of the severity of their initial infection. The lack of consensus in diagnosing Long COVID, coupled with an unclear understanding of its causes, has hindered the development of targeted therapeutic interventions.
Immunophenotyping and Cytokine Secretion Analysis
To unravel the immunological basis of Long COVID, the researchers conducted a comprehensive analysis of cytokine secretion from peripheral blood mononuclear cells (PBMCs) derived from Long COVID patients, controls, and individuals acutely infected with SARS-CoV-2. Immunophenotyping combined with intracellular cytokine staining revealed a significant increase in cluster of differentiation 8–positive (CD8+) T cell-mediated IFN-γ release in response to SARS-CoV-2 antigens.
Persistently Elevated IFN-γ Release
Unlike patients recovering from acute SARS-CoV-2 infection, Long COVID individuals exhibited persistently high levels of spontaneous IFN-γ release from CD8+ T cells. This release was found to be dependent on antigen presentation by CD14+ cells. The study emphasized the persistence of IFN-γ production in
Long Covid patients even beyond 180 days post-symptom onset, contrasting with the resolution observed in acutely infected individuals.
Cell Depletion Assays and Mechanistic Insights
The researchers employed cell depletion assays, revealing that CD8+ T cells in contact with CD14+ cells are crucial for unstimulated IFN-γ production. This mechanism was further validated through intracellular flow cytometry, confirming the predominant role of CD8+ T cells in IFN-γ release. The study identified major histocompatibility complex (MHC) class I-dependent antigen presentation by CD14+ cells as the trigger for IFN-γ release.
IFN-γ as a Potential Biomarker
The study indicated that IFN-γ could serve as a potential biomarker for Long COVID, with symptom improvement correlating with a decrease in IFN-γ production to baseline levels. Longitudinal follow-up demonstrated that individuals who did not recover from Long COVID maintained elevated levels of unstimulated IFN-γ release.
Long-Term Follow-Up and Implications
Extending the follow-up period to 31 months post-acute infection, the researchers observed a correlation between IFN-γ release and Long COVID symptoms, particularly fatigue. The study proposed classifying Long COVID based on the duration of IFN-γ signature, suggesting a potential differentiation between cases lasting over 6 months and those lasting 12 weeks.
Dysregulated Interferon Signaling and Future Directions
The study highlighted dysregulated interferon signaling as a hallmark of SARS-CoV-2 infection, specifically associated with Long COVID. The causes of persistent IFN-γ release remain under investigation, with potential factors including the persistence of viral antigens, autoantigens, and reactivation of latent herpesviruses.
Cytokine Profile and Treatment Implications
While IFN-γ stood out as the primary cytokine persistently released in Long Covid patients, the study also identified smaller increases in other proinflammatory cytokines. The findings raised the possibility of a broader cytokine dysregulation in Long Covid pathology. The implications of IFN-γ secretion as both a mediator and a biomarker for Long COVID symptoms were discussed, with potential treatment avenues and the need for further research highlighted.
Conclusion
The University of Cambridge's groundbreaking study provides a comprehensive understanding of the immunological mechanisms associated with Long COVID. The persistent and spontaneous release of IFN-γ by CD8+ T cells, dependent on antigen presentation by CD14+ cells, emerges as a potential biomarker for Long COVID. The correlation between IFN-γ levels and symptom resolution opens new avenues for diagnostic and therapeutic developments. The study not only sheds light on the intricate immunological landscape of Long COVID but also paves the way for targeted treatments and improved patient care. As the world grapples with the long-term consequences of the COVID-19 pandemic, research endeavors like these play a crucial role in unraveling the mysteries of post-acute sequelae and guiding the development of effective interventions.
The study findings were published in the peer reviewed journal: Science Advances.
https://www.science.org/doi/10.1126/sciadv.adi9379
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