Long COVID, also known as post-COVID syndrome, is a condition in which symptoms persist for months or even years after coronavirus infection. Most commonly, patients report severe fatigue, reduced concentration and memory, exercise intolerance, and cognitive impairment. Long COVID affects multiple organs and systems and is observed in more than 10% of individuals who have had COVID-19. The likelihood of developing long COVID is associated with the severity of acute COVID-19, age, sex, and the presence of chronic diseases.
The mechanisms underlying long COVID are not fully understood. Current evidence points to a combination of processes, including increased complement activation, metabolic and hormonal dysregulation, inflammatory responses, and immune system dysfunction. Proposed causes include persistent viral presence or viral remnants, autoimmune reactions, cortisol insufficiency, herpesvirus reactivation, metabolic dysfunction, T cell abnormalities, and inflammation-mediated tissue damage.
Due to the heterogeneity of symptoms, treatment of long COVID is usually individualized, with an emphasis on rehabilitation. However, the STOP-PASC clinical trial showed that a 15-day course of nirmatrelvir–ritonavir did not lead to significant improvement in symptoms such as fatigue, brain fog, or dyspnea, underscoring the need for new therapeutic strategies.
Persistent Inflammation and T Cell Exhaustion in Long COVID
Researchers from the Center for Virology and Vaccine Research (USA) compared immune and inflammatory parameters in individuals with long COVID (LC group) and in patients who recovered from infection without long-term consequences (CC group). The results showed that long COVID is associated with persistent inflammation, signs of T cell exhaustion, metabolic disturbances, and increased activity of JAK–STAT and IL-6 signaling pathways. These changes are considered key biological features of long COVID.
Participants were recruited during two periods: 2020–2021 and 2023–2024. Analyses were performed 90–180 days and up to 700 days after coronavirus infection. Clinical symptoms in the LC group included dyspnea, brain fog, fatigue, pain, cough, and changes in smell and taste perception.
Gene expression analysis in peripheral blood mononuclear cells showed increased levels of proinflammatory markers in the LC group compared with both the CC group and uninfected individuals. In the LC group, expression of proinflammatory cytokines and chemokines was elevated, including CXCL2, CXCL3, CCL3, IL10, IFNG, IL6, TNF, IL1B, IL1A, and NFKBIZ. At the same time, expression of NLRP3 inflammasome components and genes associated with the complement and coagulation systems – C5, F3, and THBS1 – was increased. Activity of IL-6, IFNα, IFNβ, IFNγ, and JAK–STAT pathways was also elevated.
Against this background, the LC group showed reduced expression of natural killer (NK) cell receptors, both activating (e.g., KLRC2) and inhibitory (e.g., KLRC1 and KIR3DL2). Markers of T cell differentiation and activation were also reduced. JAK1, JAK–STAT, and IL-6 signaling pathways correlated with CD8 T cell exhaustion and programmed cell death.
Taken together, these changes indicate a combination of persistent inflammation and T cell exhaustion. T cell exhaustion correlated with clinical symptoms in the LC group, including fatigue, dyspnea, and cognitive impairment.
In patients who later develop long COVID, increased activation of proinflammatory immune pathways is already evident during the acute phase of infection. During this period, activity of IFNβ and IFNγ signalling, the IL-6 and JAK–STAT pathways, neutrophil and monocyte activity, complement activation, and coagulation is elevated.
A machine learning model confirmed that gene expression and protein levels associated with IL-6 and JAK–STAT pathways, interferon responses, complement, and proinflammatory cytokines are among the key predictors of subsequent development of long COVID.
Chronic Inflammation in Long COVID: Analysis of Peripheral Blood Samples Collected ~2 Years After Infection
Analysis of the 2023–2024 cohort confirmed the study’s main findings. Patients with long COVID showed persistent activation of proinflammatory pathways, including IL-6, JAK–STAT, interferon, and complement signalling, as well as signs of T-cell exhaustion. At the same time, reduced activity was observed in pathways related to mitochondrial function, amino acid metabolism, and NK, T, and B cell activity.
Joint analysis of both cohorts showed that IL-6, JAK–STAT, IFNγ, complement, and antigen presentation pathways were most strongly associated with long COVID. More pronounced activation of inflammatory pathways was observed in women.
Conclusion
Long COVID is characterized by chronic activation of inflammatory pathways and T cell exhaustion that persist for more than 180 days after infection. At the same time, disturbances in amino acid and lipid metabolism, hormonal regulation, and reduced activity of pathways involved in telomere maintenance and DNA repair are observed. Impaired telomere maintenance may be associated with premature cellular aging and cell death, potentially hindering tissue recovery.
Current approaches to treating long COVID essentially aim to suppress potential residual viral replication with antiviral drugs. However, the low clinical efficacy of nirmatrelvir–ritonavir in this condition indicates the limitations of this strategy and the need for alternative approaches. The results of this study suggest that JAK–STAT, IL-6, and interferon signalling pathways, as well as metabolic mechanisms, may be promising therapeutic targets for long COVID.
Reference
Long COVID involves activation of proinflammatory and immune exhaustion pathways
