Five major mechanisms by which the virus, vRNA, and viral antigens may cause multiple and different pathologies in Long COVID patients. (A) A causative factor in a large subset of patients with LC is that reservoirs of virus, viral RNA (vRNA), and/or fragments may persist in multiple sites of the body. (B) This causes chronic inflammation, overstimulating innate and adaptive immune cells, and providing continuous viral antigenic stimuli to (C) exhausted CD4+ and CD8+ T cells [31,33,34,35,36]. This may result in damage to major organ systems, leading to neurological, cardiovascular, pulmonary, muscular, and psychiatric pathologies [43,44]. (D–F) Other possible causative factors of LC include metabolic disturbances, immune dysbiosis, micro-clotting, endothelial dysfunction [38,43,45,46,47], and the reactivation of HSV-1, HSV-2, EBV, CMV, and HHV-6 [48,49]. This Figure is created using BioRender.
Persistent viruses, vRNA, and viral antigens may trigger the hyperactivation of both the innate and adaptive immune systems, leading to chronic inflammation, T cell exhaustion, and herpesvirus reactivation, which in turn can cause multiple and diverse pathologies in patients with Long COVID. The reservoirs of virus and/or viral RNA (vRNA) may persist and replicate in various sites of the body, driving chronic inflammation and overstimulation of immune cells [31,32,33,34,35,36,37]. Persistent reservoirs of viruses and vRNA may be capable of being translated to continuously produce viral protein antigens, either locally in affected organs or distantly released into the circulation, thereby inducing both local and systemic inflammation, immune cells overstimulation, as well as the exhaustion of CD4+ and CD8+ T cells in a subset of patients with LC [23,35,38,39,40,41,42]. Reactivation of herpesviruses, such as HSV-1, HSV-2, EBV, CMV, and HHV-6, may also be a driver of LC [48,49]. This Figure is created using BioRender.
Numerous organs are affected by the virus, vRNA, and viral antigens, which persist in various cells, resulting in a range of varied pathologies in patients with Long COVID. Various anatomical locations have been identified where persistent reservoirs of virus, persistent vRNA, and, in some cases, persistent SARS-CoV-2 antigens are detected in LC patients [35,38,39,40,41,42] (Left). These reservoirs are detected either directly or through virus-specific immune responses that are maintained within cells from various tissues of patients with LC, long after the acute infection is cleared [23,31,33,34,35,36,50,51] (Right). This figure is created using BioRender.
Long COVID affects the brain, nerves, and cognitive function, presenting neurological symptoms during LC. Virus reservoirs in the brain (represented as green dots) or other remote organs may activate microglia, leading to neuroinflammation and potentially contributing to cognitive symptoms in LC [92,93,94,95,96,97]. Elevated biomarkers of neurodegeneration in the cerebrospinal fluid of patients with LC suggest ongoing neuroinflammation in patients with cognitive and mental disorders, as well as psychiatric manifestations and headaches [81,100]. Persistent systemic inflammation may lead to the production of cytokines and chemokines, including IL-6, IL-8, IL-1β, TNF-α, and IP-10 [90,91], as well as the overactivation of the immune system, T cell exhaustion, and the generation of reactive oxygen species. Increased blood–brain barrier (BBB) permeability may allow cytokines to penetrate the brain and induce neuroinflammation [92,93,94,95,96,97]. A more porous BBB may also permit direct viral invasion of the brain. Tissue hypoxia may occur due to microclot formation. Neurological symptoms of LC include cognition, psychiatric manifestations, headache, and others. These conditions are more commonly described in young adults and women. This figure is created using BioRender.
The discovery of persistent viral reservoirs has significant implications for both understanding and managing LC. The link between higher #viralload & the development of LC suggests that effective 💉& antiviral treatment , 😷 could help reduce the risk of developing LC
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