Immunomodulatory Mechanisms Underlying Neurological Manifestations in Long COVID: Implications for Immune-Mediated Neurodegeneration

Abstract

The COVID-19 pandemic has revealed the profound and lasting impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the nervous system. Beyond acute infection, SARS-CoV-2 acts as a potent immunomodulatory agent, disrupting immune homeostasis and contributing to persistent inflammation, autoimmunity, and neurodegeneration. Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by a spectrum of neurological symptoms, including cognitive dysfunction, fatigue, neuropathy, and mood disturbances. These are linked to immune dysregulation involving cytokine imbalance, blood-brain barrier (BBB) disruption, glial activation, and T-cell exhaustion. Key biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) correlate with disease severity and chronicity. This narrative review examines the immunopathological mechanisms underpinning the neurological sequelae of long COVID, focusing on neuroinflammation, endothelial dysfunction, and molecular mimicry. We also assess the role of viral variants in shaping neuroimmune outcomes and explore emerging diagnostic and therapeutic strategies, including biomarker-guided and immune-targeted interventions. By delineating how SARS-CoV-2 reshapes neuroimmune interactions, this review aims to support the development of precision-based diagnostics and targeted therapies for long COVID-related neurological dysfunction. Emerging approaches include immune-modulatory agents (e.g., anti-IL-6), neuroprotective drugs, and strategies for repurposing antiviral or anti-inflammatory compounds in neuro-COVID. Given the high prevalence of comorbidities, personalized therapies guided by biomarkers and patient-specific immune profiles may be essential. Advancements in vaccine technologies and targeted biologics may also hold promise for prevention and disease modification. Finally, continued interdisciplinary research is needed to clarify the complex virus-immune-brain axis in long COVID and inform effective clinical management.

Keywords: COVID-19; SARS-CoV-2; immune system; long COVID-19; neurological disease.

Figure 1

Schematic illustration of proposed mechanisms of neuroimmune dysfunction following SARS-CoV-2 infection. Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may trigger neuroimmune impairment through five interconnected pathways: (1) A cytokine storm increases blood–brain barrier (BBB) permeability and promotes neuroinflammation; (2) BBB disruption via oxidative stress and spike-mediated endothelial injury facilitates central nervous system (CNS) entry; (3) molecular mimicry leads to autoimmune syndromes such as Guillain–Barré syndrome (GBS) and acute disseminated encephalomyelitis (ADEM); (4) persistent glial activation contributes to brain fog, fatigue, and sleep disturbance; and (5) endothelial dysfunction causes microvascular injury and long-term neurovascular damage. IL-6, interleukin-6; TNF-α, tumor necrosis factor-alpha; IFN-γ, interferon-gamma; JAK/STAT, Janus kinase/signal transducer and activator of transcription; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; S100B, S100 calcium-binding protein B, MMP-9, matrix metalloproteinase-9; ACE2, angiotensin-converting enzyme 2; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor; WM, white matter. Different colorful dots in the cytokine storm figure represent different pro-inflammatory cytokines. The upward arrow (↑) represents increased, the downward arrow (↓) represents decreased/reduced, and ↔ represents similar/indicating.

Figure 2

Clinical algorithm for the diagnostic assessment of neuroimmune dysfunction in long COVID. This algorithm provides a six-step framework for evaluating suspected neuroimmune dysfunction in individuals with long COVID. Clinical screening and history include confirmation of prior SARS-CoV-2 infection and documentation of neurological symptoms while ruling out alternative etiologies. Symptom-based stratification categorizes patients into cognitive/neuropsychiatric, neuropathic/autonomic, or mixed symptom clusters. Core biomarker assessment encompasses inflammatory markers, e.g., interleukins-6 (IL-6) and tumor necrosis factor-alpha (TNF-α); neural injury markers, e.g., glial fibrillary acidic protein (GFAP) and neurofilament light chain (NFL); auto-antibodies; and immune cell profiling. Neuroimaging and functional testing involve magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI), fludeoxyglucose-positron emission tomography (FDG-PET) or functional near-infrared spectroscopy (fNIRS), and electroencephalography (EEG) to assess white matter changes, cortical metabolism, and electrical activity. Integrated diagnosis considers whether the phenotype is neuroinflammatory, autoimmune-mediated, neurodegenerative-leaning, or functional. Tailored management and monitoring recommend phenotype-guided therapy, serial biomarker monitoring (every 3–6 months), and referral of complex cases for specialty evaluations or clinical trial enrollment.